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Therapeutic and Diagnostic Agents for Parkinson's Disease

CNS Disorders

  1. Raymond G. Booth1,
  2. John L. Neumeyer2,
  3. Ross J. Baldessarini2

Published Online: 15 SEP 2010

DOI: 10.1002/0471266949.bmc105.pub2

Burger's Medicinal Chemistry and Drug Discovery

Burger's Medicinal Chemistry and Drug Discovery

How to Cite

Booth, R. G., Neumeyer, J. L. and Baldessarini, R. J. 2010. Therapeutic and Diagnostic Agents for Parkinson's Disease. Burger's Medicinal Chemistry and Drug Discovery. 529–568.

Author Information

  1. 1

    University of Florida, Gainesville, FL

  2. 2

    Harvard Medical School, Boston, MA

Publication History

  1. Published Online: 15 SEP 2010

1 Introduction

  1. Top of page
  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References

In 1817, British physician James Parkinson published “An Essay on the Shaking Palsy” (1) that first described clinical features of what is now the second most common neurodegenerative disorder. Parkinson's disease (PD) is characterized by resting tremor, disturbances of posture, and paucity or slowing of volitional movement. The primary etiology of PD is unknown, but its neuropathology is marked by progressive degeneration of pigmented neurons of midbrain and brainstem, mainly those that produce dopamine (DA) as a neurotransmitter in the midbrain substantia nigra and project to the forebrain extrapyramidal motor control center of the basal ganglia (caudate–putamen, and other components of the corpus striatum). There is also variable loss of other pigmented monoaminergic neurons in the brainstem, particularly those producing norepinephrine. Since the early 1960s, pharmacotherapy for PD has been based rationally on replacing the DA lost due to selective and idiopathic degeneration of DA neurons by giving large doses of its immediate metabolic precursor amino acid, l-dihydroxyphenylalanine (l-dopa). Later, synthetic DA receptor agonists and agents that inhibit the metabolic breakdown of DA (or l-dopa) were employed as well. Pharmacotherapy for PD, however, remains palliative and symptomatic, and does not address the still-elusive pathophysiological mechanisms underlying neuronal degeneration. Proposed mechanisms are based on several possibly convergent hypotheses encompassing genetic factors, oxidative metabolism associated with advancing age, and environmental factors. Current pharmacotherapy is limited in both effectiveness and tolerability, especially late in the progression of the disease. Improved symptomatic and anticipated curative pharmacotherapy depends on better understanding of the fundamental pathogenesis of PD. In this light, this chapter reviews medicinal–chemical aspects of available antiparkinsonism drugs, emerging treatments, and neuroradiological agents for diagnosis and monitoring the progression of PD.

2 Parkinson's Disease

  1. Top of page
  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References

Typically, PD presents in mid- or late life, most often at age between 55 and 65. It affects approximately 1–2% of the population elder than age 65; in the population elder than age 84, the incidence increases to 3–5% per year (2). Prevalence of PD is expected to increase substantially over the next several decades, as the population ages (3). PD presents as a classic tetrad of signs: (1) resting tremor that improves with voluntary activity, (2) bradykinesia or slow initiation and paucity of voluntary movements, (3) rigidity of muscle and joint motility, and (4) postural disturbances including falls. These signs vary in their early intensity, combinations, and progression among affected individuals. Some cases also show dyscontrol of autonomic functions mediated by the potentially affected central noradrenergic sympathetic nervous system, with losses of norepinephrine neurons of the locus coeruleus (4). Dementia is about six times more common among elderly patients with PD, and, there can be other spontaneous or treatment-associated neuropsychiatric disturbances, including hallucinations and depression (5). In fact, such neuropsychiatric symptoms lead to more nursing home placements than the motor dysfunctions of PD (6). Although l-dopa pharmacotherapy has decreased morbidity and mortality, mortality among PD patients is still approximately 60% greater than in age-matched controls (7).

Parkinsonism, as a bradykinesia syndrome, represents the clinical outcome of etiologically diverse conditions. These include idiopathic degenerative disorders (including idiopathic Lewy body dementia and multiple system atrophy with dysautonomia [Shy-Drager syndrome]), infections (including postencephalitic parkinsonism, such as from von Economo's encephalitis lethargica, that arose with influenza epidemics of the early twentieth century), effects of neurotoxins (including certain heavy metals such as manganese, pyridiniums such as 1-methyl-4-phenylpyridinium (MPP+) (Fig. 1), and the marine cyanobacteria product β-N-methylamino-l-alanine (BMAA) (8). Bradykinesia and variable tremor also are commonly associated with the use of first-generation neuroleptics as well as some modern antipsychotic agents and other DA receptor antagonists or DA-depleting agents (9, 10). The designation PD refers to the idiopathic disorder, to distinguish it from other parkinsonian syndromes (“parkinsonism”).

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Figure 1. Phenylpiperidine analgesics and metabolic activation of MPTP. In the presence of acid and heat, MPPP forms MPTP that undergoes an MAO-B catalyzed two-electron oxidation to MPDP+ MDPP+ undergoes a two-electron auto-oxidation (also can be catalyzed by MAO-B) to MPP+ that is accumulated into DA neurons by the DA transporter and subsequently into mitochondria where it disrupts cellular respiration, producing neuronal cell death.

Neuropathologically, PD is a slowly progressive neurodegenerative disorder of unknown cause that selectively affects the dopaminergic, extrapyramidal nigrostriatal pathway. The disease is characterized by gradual destruction of DA-containing neurons in the pars compacta component of the pigmented midbrain substantia nigra, leading to a deficiency of the neurotransmitter in DA nerve terminals of the corpus striatum (5). Degenerative changes in the pigmented nuclei of the noradrenergic locus coeruleus region of the midbrain-pons also can occur, and remaining catecholamine cells typically acquire intraneuronal inclusions (Lewy bodies), whose development and significance remain unclear (4, 5). The discovery of DA deficiency in postmortem brain tissue of PD patients a half-century ago, with then-emerging knowledge of DA biosynthesis and metabolism, led to the rational prediction that l-dopa 1 (Fig. 2), the immediate metabolic precursor of DA 2 (Fig. 2), would be an effective palliative agent in PD (11).

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Figure 2. Pathways in metabolism of l-dopa and its major decarboxylated product DA. Heavy and light arrows indicate major or minor reactions. AD, aldehyde dehydrogenase; AAD, aromatic l-amino acid decarboxylase; COMT, catechol-O-methyltransferase; DH, DA β-hydroxylase; MAO, monoamine oxidase; PENT, phenylethanolamine-N-methyltransferase.

2.1 Pathophysiology

The “basal ganglia” of the brain consist of five interconnected subcortical nuclei that span the telencephalon (forebrain), diencephalon, and mesencephalon (midbrain). These nuclei include the corpus neostriatum (caudate and putamen), globus pallidus, thalamus, subthalamic nucleus, and midbrain substantia nigra (pars compacta and pars reticulata). Medium-sized spiny neurons that produce the major inhibitory amino acid transmitter γ-aminobutyric acid (GABA) are principal neurons in the caudate–putamen. They receive dense input from descending corticostriatal projections mediated by the principal excitatory amino acid neurotransmitter l-glutamic acid, as well as a prominent dopaminergic input from the midbrain substantia nigra. The GABA-producing inhibitory neurons, as well as intrinsic acetylcholine-producing interneurons, of the caudate–putamen respond to DA input through several DA receptors (types D1–D4).

DA receptors are grouped into excitatory D1-types (D1 and much less prevalent D5 receptors), and inhibitory D2-types (D2 with splice variants, and less abundant D3 and D4) subfamilies of membrane proteins. These peptides, composed of 387–477 amino acids in man, are typical of the superfamily of GTP-binding protein (G-protein)-associated membrane proteins that include most monoaminergic receptors and other physiologically important membrane proteins. Their structures are characterized by seven relatively hydrophobic, putative transmembrane regions linked by four extracellular and four intracellular loop segments, starting from an extracellular amino terminus, and extending to an intracytoplasmic carboxy end of the receptor polypeptide chain (12). The third intracellular loop and carboxy-terminus segment vary most among DA receptor subtypes, and probably interact critically with excitatory or inhibitory G-proteins and intraneuronal molecular components of effector mechanisms, including adenylyl cyclase (stimulated through D1-like and inhibited by D2-like receptors) and phospholipase C (stimulated by D2 and less abundant D4, but inhibited by D3 receptors) (12).

The inhibitory spiny GABAergic neurons send projections by two major pathways that appear to exert balanced regulatory influences on the ascending thalamocortical circuits mediating control of voluntary movement through descending corticospinal projections to the spinal ventral horn motor neurons that innervate skeletal muscles. A widely accepted, but tentative and possibly over-simplified model of the basic anatomical connections of this complex is summarized schematically (5, 12-17) (Fig. 3).

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Figure 3. Circuitry of the basal ganglia. Shown are the major relationships to the neostriatum (caudate nucleus–putamen complex) with its prominent dopaminergic innervation (particularly of putamen in man) from the midbrain substantia nigra pars compacta (SNc), as well as descending control by corticostriatal glutamatergic projections. Dopamine exerts excitatory effects through D1 receptors on efferent medium spiny neurons that are GABAergic and inhibitory to the substantia pars reticulata (SNr) and the internal portion of the globus pallidus (GPi), and limit a secondary inhibitory influence of nigrothalamic and pallidothalamic GABA neurons (that also express substance P [SP] and dynorphin [DYN] peptides) to facilitate the ascending excitatory glutamatergic (Glu) thalamocortical circuits. This short outflow loop from the neostriatum is paralleled by a long loop that involves D2 DA receptors inhibitory to generally excitatory acetylcholinergic (ACh) interneurons (which are inhibited by GABA neurons) as well as to GABA efferents to the external portion of globus pallidus (GPi) and coexpress enkephalins (ENK). The globus projects GABAergic neurons that tonically inhibit excitatory glutamatergic neurons of the subthalamic nucleus (STN) that stimulate an inhibitory influence on the substantia nigra, internal globus pallidus, and PPN on the thalamus (including its ventral lateral nucleus) to yield a net reduction of thalamocortical activation. In Parkinson's disease, the nigrostriatal DA projections degenerate and dopaminergic influences in neostriatum are initially compromised and eventually lost. Loss of DA in PD reduces functions of both direct and indirect pathways to yield a net decrease in thalamocortical stimulation, with clinical bradykinesia. Excessive dopaminergic stimulation encountered in the treatment of PD increases thalamocortical activation, with clinical dyskinesias. This traditional model remains tentative and incomplete, and does not include simultaneous influences of the several D1-like and D2-like receptors at some GABAergic neurons in the neostriatum.

Output pathways from neostriatum usually are considered to include a “direct” striatonigral pathway consisting of GABAergic neurons that project directly to the pars reticulata of the substantia nigra, as well as a prominent projection to the internal (medial) portion of the globus pallidus in human brain. Another “indirect” or striatopallidal pathway involves efferent GABAergic projections from striatum that communicate through the external (lateral) globus pallidus to the subthalamic nucleus. This inhibitory influence on the subthalamic nucleus is balanced against an excitatory glutamatergic input from cerebral cortex. In turn, the subthalamic nucleus exerts an excitatory glutamatergic influence on the substantia nigra reticulata and internal (medial) globus pallidus.

Modified by these direct and indirect descending influences, the internal (medial) globus pallidus and pars reticulata send inhibitory GABAergic projections that modulate activity of ascending thalamic neurons, particularly in the ventral (mainly anterior and lateral) thalamic nuclei. The thalamic nuclei project ascending glutamatergic excitatory efferents to motor cerebral cortex, thus exerting a major regulatory influence over the descending corticospinal motor output pathway that controls the cholinergic spinal ventral motor horn cells innervating skeletal muscle (18).

DA modulates the activity of local and efferent inhibitory GABAergic neurons as well as acetylcholinergic interneurons of caudate–putamen (12, 18). Excitatory DA D1-type receptors, together with the neuropeptides substance P and dynorphin, are expressed mainly by the striatonigral GABAergic neurons in the direct output pathway. In contrast, inhibitory DA D2-type DA receptors, along with the neuropeptide enkephalin, are predominantly localized to striatopallidal GABAergic efferents of the indirect output pathway. These relationships lead to a complex role for DA in the basal ganglia. By stimulating excitatory D1 receptors, DA appears to have a net facilitatory effect on the direct GABAergic pathway to internal (medial) globus pallidus and midbrain, which can diminish their inhibitory connections to thalamus, to increase ascending excitatory thalamocortical activity. In contrast, activation of D2 receptors in the indirect pathway inhibits GABAergic neurons projecting to external (lateral) globus pallidus, thereby increasing pallidal inhibitory influence on the subthalamic nucleus. These effects result in a net inhibition of an excitatory glutamatergic link from the subthalamic nucleus to GPi/SNr that reduces pallidal GABAergic inhibition of thalamus. The outcome is to increase thalamocortical stimulation, opposite to the effect initiated by DA through the direct pathway (Fig. 3).

There are also important connections between the basal ganglia and the structures in the midbrain. The pedunculopontine nucleus (PPN) is in proximity to the mesencephalic locomotor area and consists primarily of cholinergic neurons (pars compacta) (19). The pronounced cholinergic neuronal loss found in the PPN correlates with gait dysfunction and relative immobility (akinesia) in PD. In addition, hyperactivity of the subthalamic nucleus has been demonstrated in PD and is attributed to excitatory input primarily from thalamus glutamatergic neurons (20).

In sum, the overall effect of DA is to facilitate cortical excitation by thalamocortical glutamatergic projections through the direct pathway, but to decrease thalamocortical stimulation through the indirect pathway. Accordingly, in PD striatal DA deficiency alters the modulation of excitatory outflow from ventral thalamus to motor cortex (5, 10). Presumably, a balance of D1- and D2-mediated dopaminergic function would be optimal in restoring the functional losses that follow degeneration of the DA-producing neurons. Neurochemically, striatal DA deficiency seems to account for the major motor symptoms of PD, particularly bradykinesia. Cholinergic loss may result in dysfunctional modulation of dopaminergic circuits, as well. The mainstay of pharmacological treatment (5), continues to be replacement therapy with the α-amino acid, l-3,4-dihydroxyphenylalanine (l-dopa) 2 (Fig. 2), the immediate biochemical precursor of DA, discussed below, in an effort to produce nearly physiological agonism of both D1 and D2 DA receptors.

2.2 Etiology

2.2.1 Genetic Factors

Although the neuropathology of PD is well defined, the primary cause of the neuronal degenerative changes involved remains unknown, confounding rational development of additional rational and novel symptomatic, prophylactic, or potentially curative pharmacotherapy. Several possibly convergent hypotheses are proposed regarding causes of PD, encompassing genetic factors, oxidative metabolism associated with advancing age, and environmental factors.

Given that several neurodegenerative disorders (including the hyperkinetic neuropsychiatric disorder Huntington's disease, marked by choreoathetosis, early psychiatric symptoms and progressive dementia) are genetically determined, researchers have investigated possible genetic influences in PD. Epidemiological studies have found that apart from age, a family history of PD is the strongest predictor of increased risk of the disorder (21, 22); however, shared environmental exposures in families must also be considered.

One familial form of PD is characterized by mutations in the α-synuclein gene, originally reported in a single large Italian family, three smaller Greek families, and a German pedigree (23, 24). The protein α-synuclein is a highly conserved, abundant, 140-amino-acid polypeptide expressed mainly in cerebral nerve terminals. Aggregation of α-synuclein molecules leads to pathological inclusions (synucleinopathy) that characterize many neurodegenerative disorders, including PD (25). The function of α-synuclein is not well characterized, but it appears to play a role in regulating DA homeostasis, including, modulation of DA synthesis, release, and reuptake at nerve terminals. In vitro studies using neuronal cells (26) indicate that downregulation of α-synuclein enhances DA biosynthesis, suggesting that dysfunction of α-synuclein may lead to increased intraneuronal levels of DA that become neurotoxic (see below). Nevertheless, several studies failed to detect mutations in the α-synuclein gene in large family samples (27, 28), or in studies of identical and heterozygous twins (29-31).

Mutations in four other genes—DJ-1, PINK1, parkin, and leucine-rich-repeat kinase 2 (LRRK-2)—are unequivocally associated with development of familial PD (32), and several other mutations also are implicated. Such mutations may lead to excessive production of damaged proteins or dysfunction of protein clearance mechanisms in the brain (33, 34). Under physiological conditions, damaged proteins usually are degraded and cleared by the ubiquitin–proteasome system (UPS). Increased production of damaged proteins or decreased UPS-mediated degradation and clearance may lead to protein aggregation and proteolytic stress, negatively affecting cellular structures and processes (35, 36). For example, the UPS protein parkin mediates engulfment of dysfunctional mitochondria by autophagosomes (37), and dysfunctional parkin may fail to remove dysfunctional mitochondria. PINK1 appears to function prior to parkin in the same pathway to maintain mitochondrial integrity and functioning in both muscles and dopaminergic neurons (38, 39). In cases of familial PD associated with mutations of LRRK-2 (a kinase encoding the protein dardarin), protein accumulation as well as Lewy body formation have been identified postmortem (40).

In summary, there is compelling evidence for apparently rare cases of genetically linked PD, primarily involving early onset of the disorder, however, most cases are not associated with known genetic mutations and are considered sporadic (41). Notably, however, synucleinopathy has been detected in sporadic cases of PD (42), suggesting that abnormalities of protein aggregation may be relevant to the etiology of the more common “sporadic” forms of the disease. Moreover, although PD associated with genetic mutation involves fewer than 10% of cases, their study has facilitated understanding of molecular pathways that may lead to neurodegeneration, especially involving DA neurons.

2.2.2 Dopamine and Mitochondrial Oxidative Metabolism

Oxidative metabolism involving the synthesis and catabolism of DA has been implicated in the PD disease process through production of chemically reactive products, including, epoxides (43), free radicals (44), and quinones (45, 46).

Synthesis of DA, as well as the catecholamine neurotransmitters norepineprine and epinephrine, proceed by initial 3-oxidation of the precursor amino acid l-tyrosine 3 to l-dopa in a rate-limiting step catalyzed by tyrosine hydroxylase (l-tyrosine-3-mono-oxygenase) (Fig. 2). The mechanism of this hydroxylation may involve direct insertion of an oxygen atom into l-tyrosine to form l-dopa, or through an intermediate arene epoxide 4 (43) (Fig. 4), as is case for metabolic conversion of benzene to phenol (47), and of estradiol to catechol-estrogens (48, 49). An analogous epoxide intermediate occurring during the conversion of tyrosine to l-dopa could alkylate nucleophilic functionalities on proteins, RNA, or DNA to produce neurotoxicity (49).

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Figure 4. Putative and known compounds involved in DA synthesis and catabolism, some of which may cause DA neuronal cell death.

In addition, monoamine oxidase (MAO)-catalyzed oxidation of DA and other monoamines generates hydrogen peroxide (H2O2; see Equation 1 in Fig. 4), which can undergo a redox reaction with superoxide anion radical (O2• –) in the Haber–Weiss reaction (50) to form the extremely cytotoxic hydroxy (HO ) radical (see Equation 2 in Fig. 4) capable of causing lipid eroxidation.

MAO is expressed as two isoforms, A and B. Histochemical and immunohistochemical studies reveal that in human brain MAO-A is found primarily in noradrenergic neurons whereas MAO-B is found primarily in serotoninergic and histaminergic neurons as well as in glial cells (there is no consensus on which form may predominate in brain DA neurons; (51)). A compelling link between PD etiology and MAO is that levels of MAO-B are increased in the brains of PD patients as a consequence of gliosis (52). Involvement of MAO-B in age-related neurological disorders that include PD also is suggested by observations that human and rodent MAO-B levels increase with aging (53, 54). Increased MAO-B levels would be expected not only to diminish DA levels but also to increase levels of potentially neurotoxic oxidation products (Fig. 4). Another link between MAO and PD is that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the aldehyde that is the MAO-derived 2-electron oxidation product of DA (Equation 1 in Fig. 4), has been implicated in the aggregation of α-synuclein (55).

In addition to generating potentially neurotoxic products from MAO-catalyzed oxidation of DA, auto-oxidation of DA can yield electrophilic semiquinone 5 (Fig. 4) and quinone species 6 (Fig. 4). These reactive products of oxidation are of interest because they are cytotoxic and can alkylate protein sulfhydryl groups, including glutathione (46, 56). Manganese ion also can catalyze oxidation of DA to yield quinones implicated in manganese-associated parkinsonism (45). Analysis of postmortem brain tissue from PD patients has found decreased levels of glutathione (57), increased lipid peroxidation (58, 59), and increased oxidation of DNA (60) and proteins (61).

Auto-oxidation of catecholamines also leads to formation of the polymeric pigment neuromelanin that increases with age and is responsible for the dark coloration of DA-producing cells in the substantia nigra and the norepinephrine neurons of the locus coeruleus (46). The physiologic role of neuromelanin is poorly understood. The pigment is increasingly deposited in catecholaminergic neurons with advancing age, however, and it has been suggested that its accumulation in nigral neuronal cells eventually causes cell death (4).

Mitochondrial dysfunction also is hypothesized to play a role in PD neuronal cell death (62, 63). Postmortem samples of brain and peripheral tissue from PD patients indicate selective mitochondrial complex I deficiency, including in the substantia nigra and other sites (64, 65) that might contribute to neuronal cell death in PD through decreased ATP synthesis and altered homeostasis of reactive species such as hydrogen peroxide, superoxide, and free hydroxyl radicals (62, 63). Mitochondrial dysfunction and altered oxidative metabolism of DA may converge, in that decreased energy production by mitochondria may impede vesicular storage of DA, leading to increased concentrations of free DA in cytoplasm that can auto-oxidize to quinones and semiquinones (66).

In summary, toxic chemical products associated with metabolism of DA or altered mitrochondrial function may contribute to the progressive loss of DA neurons that occurs normally with maturation and aging at a rate of approximately 13% per decade after age 45 (67-69). Clinical symptoms of PD emerge as losses of DA neurons exceed 65% (70). Conceivably, PD may result from neurodegenerative changes involving oxidative metabolism attributed to normal aging superimposed on neurotoxic insults that may occur at various ages. Such a two-factor pathophysiology might explain why PD is usually a progressive disorder of late onset (71). Hypotheses concerning the initial pathological event have centered on environmental neurotoxicants, discussed below.

2.2.3 Environmental Factors

There is evidence to suggest that environmental toxicants may cause some parkinsonism syndromes (72, 73). This hypothesis seems consistent with the fact that PD is now the second most common degenerative neuropsychiatric disorder (after the dementias), in contrast to its evident rarity in previous centuries (74). Even in disorders with strong familial association, a role of shared environmental exposures and other indirect factors may occur, in addition to any specific genetic contribution. Studies of some familial but idiopathic forms of PD-like neurodegenerative disorders in the Western Pacific (such as the prion disease Kuru and amyotrophic-sclerosis-PD-like syndromes associated with cycad plant toxins) do not support genetic or infectious etiologies, but leave open the possibility of neurotoxic factors (75, 76). A striking example of a probably neurotoxic disorder is the PD-like syndrome characterized by tremor and bradykinesia as well as dystonia and both cognitive and behavioral disturbances found among manganese miners in the Andes, and others exposed to the metal (77).

There is also evidence linking herbicides and pesticides to PD. For example, there is a remarkably high correlation between incidence of PD and use of pesticides in an agricultural region of Québec (78). Of relevance here, N,N′-dimethyl-4,4′-bipyridinium dichloride 7 (Fig. 1), better known as Paraquat, is one of the most widely used herbicides in the world (79) and has a close structural resemblance to the selective DA neurotoxicant MPP+ 8 (Fig. 1), that also was once marketed as the herbicide Cyperquat (73, 80). Like MPP+ and the pesticide rotenone (see below), Paraquat inhibits mitochondrial complex I and cellular respiration, though only at concentrations (∼10 mM) considerably higher than are required for MPP+ (∼10 μM) or rotenone (∼10 nM) (80). Some investigators have reported Paraquat-induced postmortem losses of nigral DA neurons and degeneration of striatal DA-terminals following decreased locomotor activity (81). However, others found no evidence of neurotoxic changes after exposure to Paraquat (82), and Paraquat neurotoxicity, unlike MPP+-associated parkinsonism, probably is not highly selective for DA neurons (80) (see below). Finally, the ability of Paraquat itself to gain entry to the brain remains uncertain (73).

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Another potentially relevant neurotoxicant is the lipophilic pesticide–piscicide rotenone 10. Rotenone is an isoflavone, many of which are found in roots and stems of several plants. Of note, this association with plant products allows rotenone to be labeled as “natural” and to be used in organic food farming (79). Rotenone easily crosses the blood–brain barrier and neuronal cell membranes. It appears to be capable of inhibiting mitochondrial complex I to cause highly selective degeneration of nigrostriatal DA neurons (73, 80), producing hypokinesia and rigidity as well as accumulation of fibrillar cytoplasmic inclusions that contain ubiquitin and α-synuclein (83).

One of the best-characterized epidemiological findings in PD is its lower incidence in cigarette smokers than in nonsmokers (84). Several mechanisms might account for this inverse correlation, which might enhance understanding of neuroprotection in neurodegenerative disorders and even lead to effective prophylactic or even curative pharmacotherapy. For example, activation of central nicotinic acetylcholine receptors by nicotine modulates DA neurotransmission and also reduces neural inflammation (85). Moreover, other constituents in tobacco smoke are MAO inhibitors, including, farnesylacetone, a selective inhibitor of MAO-B (86), thought to be the predominant MAO isoform responsible for metabolism of DA in brain (glial cells). Of potential relevance to the pathophysiology of PD, prolonged nicotine exposure can increase activity of the UPS system (87) discussed in Section 2.2.1.

There also is an inverse correlation between risk of developing PD and coffee and caffeine consumption (88). Caffeine is a nonselective adenosine A1/A2 receptor antagonist that reduces parkinsonism-like tremor in rodent models of PD (89). The adenosine A2A receptor subtype is expressed abundantly on medium spiny neurons, and activates intracellular kinases. Aberrant interneuronal signaling associated with these phosphate-adding enzymes has been linked to parkinsonism-like signs in rodent and primate models of PD, and with dyskinetic motor response produced by dopaminomimetic therapy in these models (90). Adenosine A2A receptor antagonists are proposed for pharmacotherapy of PD (91) and are undergoing clinical trials (see Section 3.2.2). Antagonism of adenosine A1 receptors also may reduce parkinsonism-like tremor in rodents (89), but no clinical candidate anti-A1 drugs have emerged.

In summary, there are several potential links between the PD and the environment, although their relevance to the clinical disorder remains uncertain. Some environmental factors, such as cigarette smoking and caffeine consumption, may protect against development of PD and might help to delineate biochemical mechanisms leading to effective pharmacotherapy for PD. Regarding the etiology and pathophysiology of PD, intriguing findings have arisen from epidemiologic studies of various apparent environmental or toxic risk factors for PD, including exposure to pesticides, herbicides, well water, wood pulp mills, and rural living (92, 93). Pathological mechanisms involving oxidative metabolism and environmental neurotoxicants may converge. A particularly well-studied example of such convergence involves the discovery that N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 11 (Fig. 1) produces a severe parkinsonism syndrome in humans and some laboratory animals that is remarkably similar to the idiopathic disease. As such, MPTP has been an extremely useful tool to study the etiology and pharmacotherapy of PD.

The cyclic tertiary amine MPTP 11 induces a form of parkinsonism in humans and lower primates similar in neuropathology and motor abnormalities to idiopathic PD (94-96). The role of MPTP in parkinsonian disorders was revealed by a serendipitous series of events. In 1977, a young college student suddenly developed parkinsonian symptoms with severe rigidity, bradykinesia, and mutism. The early and abrupt onset of such symptoms was so atypical that the patient initially was thought to have catatonic schizophrenia. The subsequent diagnosis of parkinsonism was substantiated by a therapeutic response to l-dopa. He admitted having synthesized and used several illicit drugs. Chemical analysis of glassware that the patient used for chemical syntheses at his home revealed several pyridines, including MPTP 11, apparently formed as by-products during synthesis of the reverse ester of the narcotic analgesic meperidine 12 (Fig. 1) known as MPPP (N-methyl-4-propionoxy-4-phenylpiperidine) 13 (Fig. 1) or “designer heroin.” MPPP is an analog of prodine, a nonopioid, synthetic analgesic, alphaprodine 14 (Fig. 1), itself an analog of the analgesic meperidine. Initially, it was unclear whether MPTP or other constituents of the injected mixture accounted for the neurotoxicity that produced parkinsonism.

After the patient returned home, he continued to abuse drugs and died of an overdose; autopsy revealed degeneration of the substantia nigra, the hallmark neuropathological feature of PD. Subsequently, other patients were identified with virtually identical parkinsonian symptoms who had also been taking intravenous injections of preparations of MPPP containing varying amounts of MPTP. In several patients, MPTP was the principal or sole constituent injected, implicating MPTP as a parkinsonism-producing neurotoxicant. The clinical and neuropathological features of MPTP-induced parkinsonism resemble idiopathic PD more closely than any other reported animal or human condition elicited by toxins, metals, viruses, or other means. Understanding the molecular pathophysiology of MPTP neurotoxicity has shed light on neurodegenerative mechanisms that may be present in idiopathic PD.

The chemical structure of MPTP suggests that the compound would be relatively chemically inert since it lacks a highly reactive functional group. However, MPTP can undergo metabolic activation to more reactive species. The oxidative enzyme, MAO-B, in brain tissue catalyzes the two-electron oxidation of MPTP at the allylic α-carbon to give the unstable intermediate product, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) 15 (Fig. 1). This intermediate undergoes a two-electron oxidation to the stable 1-methyl-4-phenylpyridinium species 8 (Fig. 1) via auto-oxidation, disproportionation, and MAO-B catalysis (97-99) (Fig. 1). MAO-B inhibitors can prevent MPTP-induced parkinsonism in primates (100). Although a role for the unstable dihydropyridinium species MPDP+ has not been ruled out, MPP+ is currently considered the major metabolite of MPTP responsible for DA neuronal cell death.

The α-carbon oxidation of tertiary amines, such as MPTP, by MAO (type A or type B) is surprising in view of its assumed natural preference for monoamine substrates, notably including the neurotransmitters DA, norepinephrine, and serotonin. However, MAO might be of additional physiological importance in regulating the oxidation state of pyridine systems, such as those involving nucleic acids and NADH (101), that may be involved in the neurotoxicity of MPTP (see below).

Extensive metabolic, biochemical, and toxicologic investigations have established that the nigrostriatal neurodegenerative properties of MPTP are mediated by the MAO-B derived metabolite, MPP+ This bioactivation reaction, however, probably proceeds outside of the target nigrostriatal DA neurons. The isoform of MAO, if any, inside DA neurons is not established (102, 103). Instead, MAO-B rich glial cells near striatal nerve terminals and nigral cell bodies probably oxidize MPTP to MPDP+ The conjugate base MPDP presumably diffuses out of glial cells and subsequently oxidizes to MPP+ that is sequestered into striatal dopaminergic nerve terminals via the DA neurotransporter, which accepts MPP+ as a substrate (Fig. 1) (104). Within DA neurons, MPP+ is concentrated in the mitochondria, where it selectively inhibits complex I of the electron transport chain, inhibiting NADH oxidation and eventually depleting the nigrostriatal neuronal cell of ATP (105, 106). Thus, the currently accepted mechanism of nigrostriatal cell death induced by MPTP (via MPP+) is inhibition of mitochondrial respiration (107, 108).

Several sequential factors may account for selective damage of nigrostriatal DA neurons by MPTP (Fig. 1). First, MPTP binds selectively to MAO-B, which is highly concentrated in glial cells in human substantia nigra and corpus striatum. Then, MPP+ produced from MPTP is selectively accumulated by DA neurotransporters into DA cell bodies in the SN and DA nerve terminals in striatum. Finally, within nigral cell bodies, MPP+ binds to neuromelanin, and may be gradually released in a depot-like fashion, maintaining a toxic intracellular concentration of MPP+ that inhibits mitochondrial respiration.

The serendipitous discovery and subsequent scientific investigation of the mechanism of parkinsonism produced by MPTP refocused study of the etiology and pathogenesis of idiopathic PD. For example, discovery of the selective ability of MPTP to induce nigral cell death has stimulated broad interest in identifying potential environmental or endogenous toxicants that may be causative agents in PD, as discussed above. Likewise, the mechanism of MPP+ to cause DA cell death via inhibition of mitochondrial respiration provides support for theories involving mitochondrial dysfunction and oxidative metabolism in general (oxidative stress) in the etiology of idiopathic PD (see above). Delineation of the neurobiochemical mechanism of MPTP-induced parkinsonism also has led to new pharmacotherapeutic approaches aimed at slowing neurodegeneration in PD, focusing, notably, on MAO-B and oxidative stress. Clinical studies to evaluate the effectiveness of coadministration of an MAO-B inhibitor plus the antioxidant vitamin E to slow progression of neurodegeneration in PD, however, have not yielded encouraging results (109-111). In fact, as indicated in the next section, despite progress toward understanding the etiology and pathophysiology of PD summarized above, no treatment has conclusively been proved to stop or even reliably slow the progressive neurodegeneration in the disease (112).

3 Parkinson's Disease Pharmacotherapy

  1. Top of page
  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References

3.1 Dopaminergic Pharmacotherapy

Due to the failure of various neuroprotection strategies to provide unequivocal disease-modifying benefit for PD patients (112), the mainstay of PD pharmacotherapy continues to be palliative or symptomatic, involving replacement of the DA deficiency in striatum. This is accomplished currently by one or more of the following means: (1) augmentation of the synthesis of brain DA, (2) stimulation of dopamine release from presynaptic sites, (3) direct stimulation of dopamine receptors, (4) decreasing re-uptake of dopamine at presynaptic sites, or (5) decreasing metabolism of DA or its precursor l-dopa. Some of these treatments, notably, DA receptor agonists and MAO-B inhibitors (decrease DA metabolism), might also provide neuroprotective benefit, but such effects are not well established (112).

3.1.1 l-Dopa Therapy

More than 40 years after its introduction, levodopa or l-dopa 1 (Fig. 2) remains the most effective symptomatic pharmacotherapy for PD (112). Despite controversy regarding long-term efficacy, adverse effects, and even potential neurotoxicity of this amino acid precursor of DA, most PD patients derive a substantial benefit from l-dopa throughout their illness. Moreover, l-dopa increases life expectancy among PD patients, particularly if instituted early in the illness course (113).

In 1960, Ehringer and Hornykiewicz assayed DA in the brains of patients dying with PD and found that tissue concentrations of DA in the corpora striata of many of these patients averaged only 20% of normal (114). Signs of PD in patients resembled behavioral changes in rats treated with reserpine or other amine-depleting agents. These findings led Birkmeyer and Hornykiewicz to administer high oral doses of racemic dopa to PD patients in Vienna in 1960 (115). Subsequent clinical trials led by Barbeau in Montréal in the early 1960s (116) and by Cotzias in New York in the late 1960s (117) confirmed this effect of racemic dopa. Barbeau and Cotzias, also demonstrated the greater potency and safety of the physiological enantiomer l-dopa (118, 119).

Development of l-dopa 1 (Fig. 2) as a therapeutic agent in PD is a rare example of a rationally predicted and logically pursued clinical treatment in a neuropsychiatric disorder, based on neurochemical pathology and basic pharmacological theory (11). The effectiveness of l-dopa treatment requires its penetration into the central nervous system (CNS) and local decarboxylation to DA. DA does not cross the blood–brain diffusion barrier because its amino moiety is protonated under physiological conditions (pKa = 10.6 [NH2]), making it excessively hydrophilic (120). However, its precursor amino acid l-dopa is less basic (pKa = 8.72 [NH2]) and polar at physiological pH, and so more able to penetrate the CNS, in part facilitated by transport into brain with other aromatic and neutral aliphatic amino acids (120-122).

l-Dopa is normally a trace intermediary metabolite in the biosynthesis of catecholamines, formed from the essential amino acid l-tyrosine in a rate-limiting hydroxylation step by tyrosine hydroxylase (tyrosine-3-mono-oxygenase), a phosphorylation-activated cytoplasmic mono-oxygenase. l-Dopa is readily decarboxyated by the cytoplasmic enzyme l- aromatic amino acid decarboxylase (“dopa decarboxylase”) to form DA 2. The effects observed after systemic administration of l-dopa have been attributed to its peripheral and cerebral metabolites, mainly DA, with much less conversion to norepinephrine by β-hydroxylation, or epinephrine formed by N-methylation of norepinephrine by phenylethanolamine-N-methyltransferase (120, 122) (Fig. 2). A small amount of l-dopa is O-methylated by catechol-O-methyltranferase (COMT) to l-3-O-methyldopa (l-3-methoxytyrosine), which accumulates in the CNS because of its long half-life. However, most exogenous l-dopa is rapidly decarboxyated to DA in peripheral tissues, including liver, heart, lung, and kidney. Because only about 1% of an administered dose reaches the brain, l-dopa, by itself, has very limited dose effectiveness (123). In humans, appreciable quantities of l-dopa enter the brain only when administered alone in doses (3–6 g daily) high enough to compensate for losses caused by peripheral metabolism.

l-Dopa peripheral decarboxylaton can be competitively inhibited (124) by coadministration of carbidopa (2S-3-[3,4-dihydroxyphenyl]-2-hydrazino-2-methylpropanoic acid 16 combined with levodopa in Sinemet and other products) or benserazide (2-amino-3-hydroxy-N ′-[2,3,4-trihydroxybenzyl]-propanehydrazide 17 combined with l-dopa in Prolopa and others, in countries other than the United States). Such polar decarboxylase inhibitors do not appreciably penetrate the brain to inhibit cerebral decarboxylase, thus, markedly increasing the proportion of l-dopa that reaches the brain for conversion to DA, allowing for 2.5–30-fold lower dose (0.2–1.2 g/day) of l-dopa (17). Patients with PD are typically started on a combination product, either alone or with other adjunctive agents discussed below. Products containing extended-release preparations of decarboxylase inhibitors should provide more sustained benefits with less “wearing off” of benefit after several hours, but the bioavailability and performance of these products is variable. In general, tissue uptake of l-dopa is highly dependent on competition with other aromatic and neutral aliphatic amino acids, and can be decreased substantially by a protein meal.

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Pyridoxine (vitamin B6) is the cofactor for aromatic amino acid decarboxylase. In high doses, B6 can reverse the therapeutic effects of l-dopa by increasing peripheral decarboxylase activity. However, competitive blockade of peripheral decarboxylation with carbidopa or benserazide minimizes this potential effect of pyridoxine.

DA is relatively rapidly metabolized to its principal inactive by-products by MAO (particularly MAO-A in mitochondria of aminergic nerve terminals) and by extraneuronal COMT. Tissue concentrations of the methyl-donor cofactor of methylpherases, S-adenosyl-l-methionine (SAMe), can be depleted with large doses of l-dopa (125). The main by-products of DA are 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) (3-methoxy-4-hydroxyphenylacetic acid) (Fig. 2).

Common adverse effects of l-dopa therapy are nausea and vomiting, possibly because of gastrointestinal irritation as well as stimulation by DA (and perhaps l-dopa) of the chemoreceptor trigger zone (CTZ) in the area postrema of the brainstem, an emesis-inducing center that is largely unprotected by the blood–brain diffusion barrier. An important advantage of combining l-dopa with a peripheral decarboxylase inhibitor, in association with the marked reduction of required doses of l-dopa, is less risk of emesis or other adverse effects, associated with peripheral formation of excess DA. These can include activation of peripheral adrenergic and DA receptors, in part by releasing endogenous adrenergic catecholamines (121), with a variety of cardiovascular effects. Theoretically, vasoconstriction and hypertension might occur by stimulation of peripheral α-adrenoceptors, tachycardia by stimulation of cardiac β-adrenoceptors, and direct renal and mesenteric vasodilatation by DA, although DA agonists and l-dopa usually induce hypotension. However, such effects are rarely encountered clinically with the use of a peripheral decarboxylase inhibitor with l-dopa (17).

After about 5 years of continuous treatment with l-dopa, at least half of PD patients develop fluctuating motor responses, and nearly three quarters do so by 15 years (126). These fluctuations (so-called “on–off” effects) include “off” periods of immobility, and “on” periods with abnormal involuntary movements or dyskinesias (Fig. 3). These phenomena may reflect progression of the disease with more severe striatal nerve terminal degeneration and further loss of DA, along with increased sensitivity of its receptors.

Psychiatric disturbances such as hypersexuality, mania, visual hallucinations, and paranoid psychosis also are quite common, and sometimes severe adverse responses to treatment with l-dopa or direct DA agonists. Such behavioral disturbances probably reflect excessive stimulation of DA receptors in mesolimbic or mesocortical DA systems. They can greatly complicate clinical management of PD patients, including those with clinical depression commonly associated with PD, or dementia that sometimes arises in late stages of the disease. Modern antidepressants usually are well tolerated, with inconsistent and probably minor risk of worsening bradykinesia with serotonin-enhancing antidepressants (126). Use of antipsychotic drugs, however, is limited to those with minimal risk of worsening bradykinesia and other aspects of extrapyramidal motor dysfunction (127, 128). Clozapine, though potentially toxic and relatively expensive, is best tolerated and may have particular efficacy for visual hallucinations in PD patients. Moderate doses of quetiapine and possibly of ziprasidone are sometimes tolerated, but their efficacy is not established, and other second-generation antipsychotic agents including olanzapine, risperidone, paliperidone, and even the DA partial agonist aripiprazole usually are poorly tolerated by PD patients owing to increased bradykinesia (127-131).

3.1.2 Drugs Targeting Dopamine Receptors
3.1.2.1 Dopamine Receptor Structure and Function

Recombinant DNA techniques have led to cloning and characterization of five different human DA receptors (number of amino acids in human): D1 (446), D2 short (414), D2 long (443), D3 (400), D4 (387), and D5 (477) (12). DA receptors are members of the superfamily of G protein-coupled receptor (GPCR) cell-surface proteins. GPCRs have inherent structural flexibility and numerous thermodynamic conformations (132). In addition to GPCR conformations that are constitutively active, agonist ligands can bind and stabilize or induce receptor conformations that lead to activation of the associated heterotrimeric (α, β, γ) guanine nucleotide binding (G) proteins (132). Upon activation, the α-subunit of the G-protein releases GDP in exchange for binding of GTP, and, dissociation of the β/γ-dimer from the α-monomer occurs. Various intracellular signaling molecules then can be activated by the α- as well as β/γ-subunits to result in multiple physiological and/or psychological effects (and side effects, where drug therapy is concerned).

The same GPCR can couple to different Gα proteins to result in “multifunctional” signaling (133), which has been associated with “GPCR permissiveness” resulting from a high degree of flexibility in interactions among ligands, receptors, and G proteins (134). Based on a “stimulus trafficking” hypothesis, GPCR multifunctional signaling requires heterogeneity of active receptor conformations, and some specificity of agonist ligands to induce, stabilize, or select among receptor conformations (135). Of particular relevance for medicinal chemistry, structural parameters of agonist-ligands are very important determinants of GPCR conformation that influence the type of Gα protein and the signaling pathway activated. Thus, ligand stereochemistry or other more subtle structural parameters can result in differing, ligand-specific functional outcomes (136, 137) that is referred to as “functional selectivity” (138-140).

A clinically relevant example of functional selectivity concerns the atypical antipsychotic drug aripiprazole that interacts with the dopamine D2 receptor to produce antagonist, inverse agonist, or agonist functional effects, depending upon the D2 receptor cellular milieu (e.g., G protein complement and concentration) and particular location (e.g., presynaptic versus postsynaptic, and, extrapyramidal versus limbic brain regions) (141). Functionally selective agonists targeting D2-type and/or perhaps D1 DA receptors hold the promise of correcting motor deficits without necessarily causing psychiatric and other side effects. As mentioned above, however, aripiprazole, in fact, lacks efficacy for PD-related psychoses and exacerbates PD motor symptoms (128, 130).

The thermodynamic flexibility of GPCRs manifests as thermal instability when attempts are made to extract the protein from lipid membranes with a detergent, making crystal generation difficult. Currently, the only human GPCR X-ray crystal structures solved are for the β2-adrenergic (142) and adenosine A2A (143) receptors. As there is currently no validated three-dimensional orientation of the amino acid residues at the ligand binding site for D1- or D2-type DA receptors, rational design of selective DA receptor agonists (and antagonists) is guided primarily by quantitative structure–activity relationship (QSAR) studies based on probe molecules, and ligand docking molecular modeling based on homology of DA receptors to the crystal structure of bovine rhodopsin, a particularly well-characterized GPCR (144-146). DA molecular interactions with the β2-adrenergic receptor have been extensively studied (147, 148), and it is likely DA receptor homology models will be refined based on information gleaned from the β2-receptor crystal structure.

Little information can be gained concerning the conformational requirements for DA receptor activation using DA itself because its ethylamine side chain has unlimited flexibility, and there is unrestricted rotation about the β-carbon–phenyl bond (Fig. 5). Accordingly, compounds in which the catechol ring and the amino-ethyl moiety of dopamine are held in rigid conformation have been synthesized to probe molecular determinants for receptor binding and activation. Such rigid analogs include aporphines, notably starting with the morphine acid-rearrangement product, R-(–)-apomorphine 18 (Fig. 5). The alkaloid apomorphine has been employed in experimental neuropharmacology since the late nineteenth century (149, 150). The trans-α-rotamer conformation of DA (Fig. 5) most closely aligns with apomorphine, as confirmed by the X-ray crystal structure of apomorphine (151). In contrast, R-(–)-isoapomorphine 19 (Fig. 5) mimics the structure of DA in the trans-β-rotameric conformation, and has less DA-agonist activity than apomorphine. The analog R-(–)-1,2-dihydroxyaporphine 20 (Fig. 5), mimics the cis-α-rotamer conformation of DA and is inactive (152). In addition to the aporphines, the semirigid aminotetralin, 2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) 21 (Fig. 5), that has a trans-α-rotamer conformation between the benzene ring and the amino side chain, is a more potent DA agonist than its 6,7-dihydroxy congener (A-6,7-DTN) 22 (Fig. 5) with a trans-β-rotamer conformation (153)). Studies of these rigid dopaminomimetic compounds suggest that the preferred conformation of dopamine is the extended trans conformation (α- or β-rotamer). Results from mutagenesis, molecular modeling, and computational chemistry indicate that ligand activity at D1 versus D2 receptors is critically dependent on the position of protonated nitrogen moieties of candidate ligands (as in the trans-conformation of DA) that can support high-affinity ionic bonding at a proposed anionic aspartic acid residue in the third transmembrane α-helix (D3.32), as a preferred docking site of DA receptors (144, 154, 155).

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Figure 5. Conformations of dopamine in the trans-α-rotameric, trans-β-rotameric, and cis-rotameric forms, and their structural relationships to the rigid DA analogs apomorphine, isoapomorphine, and 1,2-dihydroxyaporphine. Also shown are the corresponding semirigid dihycroxyaminotetralin analogs of DA, A-5,6-DTN and A-6,7-DTN.

3.1.2.2 Aporphine-Type Dopamine Receptor Agonists

R-(–)-Apomorphine hydrochloride was resurrected as a useful adjunct in the therapy of PD a decade ago (156), following years of neglect after promising early observations (117, 157). Lack of oral bioavailability, short duration of action, and potent central emetic action discouraged its clinical use. Nevertheless, in 1993, R-(–)-apomorphine received regulatory approval in the United Kingdom for control of refractory motor dysfunction and wide fluctuations in responses (“on–off” syndrome) to l-dopa or DA agonists (158-160). Improved motility in response to an acute challenge dose of apomorphine also can predict responsiveness to l-dopa treatment (161, 162). R-(–)-Apomorphine is an agonist for both D1- and D2-type DA receptors. With a pKa of about 9, it is mostly protonated at physiological pH, but sufficiently lipophilic to cross the blood–brain barrier readily. Apomorphine can be administered subcutaneously by intermittent self-administration with a small self-injector (Penject), or continuous infusion with a portable minipump. Catechol-diester and methylenedioxy prodrugs of apomorphine limit first-pass metabolic inactivation, while retaining much of the activity of catecholaporphines or yielding the free catechols by metabolism of the prodrugs (163). The 11-monohydroxy congener of the potent DA agonist R-(–)-N-n-propylnorapomorphine 23 (Fig. 6), R-(–)-N-n-propyl-11-hydroxynoraporphine 24 (Fig. 6), retains the critical free hydroxyl group analogous to the meta-3-hydroxy substituent of DA; the monohydroxyaporphine has potent dopaminergic activity and is orally bioavailable (163-166).

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Figure 6. Clinically used dopamine receptor agonists.

Several other agents with direct DA receptor agonist activity currently are used or are under clinical evaluation for treatment of PD (Fig. 6). These agents for the most part do not exploit known differences in molecular determinants for selective binding and function at D1- versus D2-type DA receptors (144, 167, 168), but most of those shown (Fig. 6) are at least partially D2-selective.

3.1.2.3 Ergot-Type Dopamine Receptor Agonists

Bromocriptine 25 (Fig. 6) is an ergot alkaloid-peptide that is a partial agonist at D2 and D3 DA receptors (169) that lacks appreciable activity at D1- or D4-receptors (170). It was the first direct DA agonist to be employed in the treatment of PD, after its development for use at lower doses as a prolactin inhibitor (171). Bromocriptine inhibits prolactin release from anterior pituitary mammotrophic cells that selectively express D2 DA receptors. These receptors respond to DA produced in the arcuate nucleus of the hypothalamus and released at the median eminence into the hypophysioportal blood vessels, and carried to the pituitary to act as a prolactin-inhibitory hormone. Bromocriptine is an effective prolactin inhibitor at daily doses of 1–5 mg, for which it is used to treat hyperprolactinemia associated with pituitary adenomas, or to suppress prolactin output in prolactin-sensitive metastatic carcinoma of the breast. The D2 partial agonist acts as an agonist at pituitary D2 receptors that are normally in a high sensitivity state. At daily doses of 10–20 mg, bromocriptine and other D2 partial agonist ergolines act as D2 agonists with antiparkinson and perhaps mood-elevating effects. This agonism evidently reflects the supersensitized status of denervated DA receptors in PD (172, 173). Bromocriptine is absorbed after oral administration, but approximately 90% undergoes extensive first-pass hepatic metabolism; the remainder is hydrolyzed in the liver to inactive metabolites eliminated mainly in bile, and the overall elimination half-life is approximately 3 h.

Another ergoline, cabergoline 26 (Fig. 6), is a full agonist at D2 receptors and a partial agonist at D3- and D4 -receptors, without appreciable activity at D1-type receptors (169, 170), and a relatively long half-life of approximately 48 h (5). Cabergoline was superior to placebo for treating motor signs of PD, but its comparative efficacy versus l-dopa is poorly documented (174). Lisuride 27 (Fig. 6) is an ergoline partial agonist at D2-, D3-, and D4-receptors with little activity at D1-receptors (169, 170). This relatively short-acting agent is being evaluated in patients with advanced PD, using either patch or infusion delivery methods (5, 175).

The peptide component of bromocriptine evidently is unnecessary for dopaminergic activity. Pergolide 28 (formerly, Permax®) was the first nonpeptide ergoline used successfully to treat PD, as well to inhibit release of prolactin (171, 176). Pergolide shows greater agonist effects at both D2- and D1-type DA receptors than bromocriptine does show, but it was withdrawn from clinical use due to association with valvular heart disease (177, 178). This adverse cardiac effect may be due to activation of serotonin 5-HT2B receptors by pergolide, as has been hypothesized for other drugs with potent 5-HT2B agonist activity, including, carbergoline 26 (Fig. 6) (179, 180). Moderate cardiac tricuspid valve regurgitation was more frequent in patients taking cabergoline repeatedly in relatively high doses for PD than in newly exposed or untreated controls (181). However, doses of cabergoline used to treat hyperprolactinaemia are much lower (182) and may avoid valvular heart disease (182, 183). Ergolines such as bromocriptine 25 (Fig. 6) and lisuride 27 (Fig. 6) that lack 5-HT2B agonist activity do not seem to induce cardiac valvular damage (178, 184, 185).

3.1.2.4 Other Small-Molecule Dopamine Receptor Agonists

Currently, pramipexole 29 (Fig. 6) and ropinirole 30 (Fig. 6) are among the most commonly prescribed direct DA agonists for PD in the United States (17). They were introduced primarily for advanced stages of PD to limit fluctuations in response to l-dopa therapy, and as a “rescue” therapy when l-dopa became insufficiently effective. These direct D2 DA-agonists are relatively well tolerated. Moreover, there has been concern that l-dopa might add further toxic damage to DA neurons through formation of reactive oxidized by-products. These characteristics have encouraged the use of these agents as first-line treatments, sometimes before l-dopa is added. An additional advantage of these agents is that they have relatively prolonged dopaminergic actions (long half-life), to provide more sustained clinical benefit with less risk of fluctuation of neurological status than with l-dopa, even as modified by cotreatment with inhibitors of its peripheral metabolism by decarboxylase and COMT. This impression is supported by controlled comparisons of both direct agonists with l-dopa (176). A recent study in patients initially treated with pramipexole demonstrated a reduction in loss of radiolabeled striatal nerve terminals labeled by the DA-transporter-selective radioligand [inline image]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane (β-CIT) 31 (see Fig. 7), a marker of DA neuron degeneration (186).

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Figure 7. Radioligands for dopamine neurons. These include [inline image]-dopa and nonhydrolyzable, long-acting phenyltropane analogs of cocaine, which bind selectively to DA-transporter proteins and are highly selective markers of DA neurons. These agents are useful for imaging with [inline image] for PET and [inline image] for SPECT.

Rotigotine 32 (Fig. 6) is a relatively new, nonergoline, synthetic DA agonist that is administered by transdermal patch, and used to treat both early and advanced PD (187). Like apomorphine, rotigotine is an agonist at D1 as well as D2 and D3 receptors (188). It is highly lipophilic and undergoes extensive first-pass hepatic clearance when given orally, encouraging use of the long-acting transdermal patch formulation (188). Rotigotine provides benefits in PD both alone and combined with l-dopa and is better tolerated than other DA agonists (189-191).

The direct DA agonists generally produce similar adverse effects, including initial nausea and vomiting, postural hypotension, and fatigue. These effects are especially likely with the ergolines, which are started in low doses and increased slowly, as tolerated; ropinirole and pramipexole usually can be dosed more rapidly to clinically effective levels. Additional risks include psychotic reactions when DA agonists are given alone or with l-dopa. These reactions include hallucinations, delusions, and confusion, suggesting delirium, and are most likely in elderly PD patients with symptoms of dementia. Treatment is similar to psychotic reactions encountered during l-dopa therapy, and usually includes use of low doses of such antipsychotic agents as clozapine or quetiapine (126, 173, 192). Adverse peripheral and central dopaminergic effects, including nausea, hypotension, and agitation also occur with ropinirole and pramipexole. They also can produce paradoxical somnolence as well as edema, and have been associated with uncommon narcolepsy-like, daytime sleep attacks, with potential risk during driving (193).

3.1.2.5 Experimental Dopamine D1 Receptor Agonists

The opposing actions of the direct and indirect pathways in the basal ganglia (Fig. 3) suggest that coordinated neurotransmission requires activation of the direct pathway and attenuation of the indirect pathway involving DA neurotransmission in the basal ganglia. Such neuromodulation may require a balance of stimulatory actions at D1-type receptors and inhibitory actions at D2-type receptors. Consistent with a role for D1 receptors in the direct output pathway, their stimulation represents a plausible pharmacotherapeutic approach for PD. Clinical trials in PD with early, selective D1 partial agonists such as the benzergoline CY-208-243 33 (Fig. 8) and the R-(+)-phenylbenzazepine SKF-38393 34 (Fig. 8) found these drugs to be either short-acting or ineffective, suggesting that full D1 agonist activity may be required (194, 195). Several analogs of SKF-38393 are full-efficacy D1 agonists, including R-(+)-SKF-81297 35 (Fig. 8) and its 6-halo derivatives, 6-Br-APB 36 (Fig. 8) and 6-Cl-APB (SKF-82958) 37 (Fig. 8) (196, 197). In MPTP-lesioned monkeys, 6-Cl-APB 37 produced antiparkinson effects (198), but its duration of action was less than 1 hour (198) and it produced severe dyskinetic effects (200). Moreover, R-(+)-SKF-81297 35, as well as, the benzophenanthridine dihydrexidine 38 (Fig. 8) (199), showed beneficial results only in monkeys with severe parkinsonism. It has been suggested that long-acting D1 agonists may be most useful in late stages of PD (201).

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Figure 8. Representative experimental D1 agonists. These agents have unproved or untested clinical utility in the treatment of PD.

Dihydrexidine 38 (Fig. 8) was the first full-efficacy D1 agonist to be developed, although it also has some D2-type activity (202, 203). In MPTP-lesioned monkeys, dihydrexidine essentially eliminated all parkinsonian signs, and this effect was fully blocked by a selective D1 antagonist but not by a selective D2 antagonist (204). Continuous administration of dihydrexidine to rats for 2 weeks produced very little change in D1 receptor density or D1 receptor-mediated DA-stimulated adenylyl cyclase activity, suggesting that tolerance might not develop to its antiparkinson effects. In PD patients, however, dihydrexidine has a narrow therapeutic index, with dose-limiting adverse effects that include flushing, hypotension, and tachycardia after single intravenous doses (205).

A D1 receptor pharmacophore model developed for dihydrexidine was used to design other novel molecular structures as full-efficacy D1 agonists (206). These D1 agonists include dinapsoline 39 (Fig. 8) (207) and several other analogs modeled on dihydrexidine 38 or dinapsoline 39. They include the dihydrexidine isostere A-86929 40 (Fig. 8) and its diacetyl prodrug ABT-431 41 (Fig. 8); both are full D1 agonists with sustained antiparkinson effects in MPTP-lesioned monkeys (208). In PD patients, ABT-431 was highly effective against bradykinesia, but produced dyskinesias (209).

Several isochromans also are full D1 agonists. In primates pretreated with MPTP, an early compound of this type, A-68930 42 (Fig. 8), produced seizures, but an analog, A-77636 43 (Fig. 8), showed antiparkinson effects without inducing seizures (210). However, A-77636 showed rapid desensitization to its beneficial effects (211), possibly related to its prolonged action (>20 h; (200)). Other conformationally restricted analogs containing the β-phenyldopamine pharmacophore continue to be reported, including, some with impressive D1-type over D2-type receptor agonist activity (212), however, in vivo studies with D1-agonists have given disappointing results.

3.1.3 Monoamine Oxidase Inhibitors

Given the role of MAO in catabolism of DA (Fig. 2), possibly, leading to neurotoxic oxidation products of both endogenous (Fig. 4) and exogenous (Fig. 1) substrates, MAO inhibition has the potential to boost levels of brain DA and prevent formation of damaging MAO-derived oxidation products. Furthermore, by reducing the oxidation of DA, MAO inhibitors can extend the duration of response to l-dopa, and allow use of lower doses (109). Long-acting, irreversible, nonselective MAO-A/B inhibitors, such as phenelzine 44 (Fig. 9) and tranylcypromine 45 (Fig. 9) (208, 213) are contraindicated in combination with l-dopa because of the risk of inducing hypertensive crises and delirium (17). Human brain MAO-A is found primarily in noradrenergic neurons and MAO-B is found primarily in serotoninergic or histaminergic neurons and in glial cells, and the MAO isozyme present in DA nerve terminal remains uncertain (51). There is uncertainty as to whether to target MAO-A or -B for the treatment of PD, and less is known about the structural requirements for highly specific reversible MAO-A inhibitors (214) compared to selective MAO-B inhibitors, several of which produce clinical benefits in PD.

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Figure 9. Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibitors.

Selegiline (l-deprenyl; R-[–]-N,2-dimethyl-N-2-propynyl-phenethylamine) 46 (Fig. 9) and rasagiline 47 (Fig. 9) are propargylamine-type selective irreversible inhibitors of MAO-B. In addition to potentiating DA actions and allowing for reduction of l-dopa dose, it has been proposed that MAO-B inhibitors may prevent formation of neurotoxic oxidation products of DA and slow neurodegeneration in Parkinson's disease; however, data from recent clinical studies do not support this attractive “neuroprotective” hypothesis (109-112). Nevertheless, MAO-B inhibitors have a beneficial effect on motor fluctuations because of their levodopa-sparing effect (109). Selegiline and rasagiline undergo extensive hepatic metabolism. Selegiline is N-dealkylated via CYP2B6 and CYP2C19 to (–)-methamphetamine and, subsequently, to (–)-amphetamine, which has vasoactive activity similar to (+)-amphetamine (215). The amphetamine metabolites of selegiline may contribute to its other pharmacological property of DA and norepinephrine reuptake inhibition, thus potentiating the pharmacological effects of l-dopa (107). The amphetamine metabolites of selegiline have been associated with cardiovascular (orthostatic hypotension) and psychiatric (hallucinations) side effects. Rasagiline is N-dealkylated primarily by CYP1A2 to (R)-1-aminoindan, which does not have vasoactive activity (215). Recently, rasagaline underwent clinical trials to carefully assess (controlled for confounding variables, both symptomatic and pharmacologic) its ability to provide neuroprotection (216). Rasagiline at a dose of 1 mg/day met endpoints consistent with a disease modifying (neuroprotective) effect, but, rasagiline at 2 mg/day failed—the authors of the study hypothesize that the stronger symptomatic effect of the higher dose masked an underlying disease modifying effect.

Safinamide 48 (Fig. 9) is an α-aminoamide derivative that is a reversible selective MAO-B inhibitor shown to provide benefits in early PD (217, 218). In addition to its MAO-B inhibitor properties, safinamide also blocks voltage-dependent sodium and calcium channels, and, inhibits glutamate release (217). It is currently in Phase 3 trials in the United States and in Europe (5).

3.1.4 Catechol-O-Methyltransferase Inhibitors

The peripheral metabolism of l-dopa given alone leads to very limited access of the amino acid to the CNS. It is rapidly decarboxylated by l-aromatic amino acid decarboxylase and 3-O-methylated by COMT. In addition to potentiating l-dopa with peripheral decarboxylase inhibitors including carbidopa and benserazide, there are also inhibitors of COMT. This methyl-pherase, with its methyl-donor cofactor SAMe, converts l-dopa and catecholamines preferentially to their m-methoxy derivatives (Fig. 2). These include 3-O-methyl-dopa and 3-O-methyl-DA (3-methoxytyramine, 3-methoxy-4-hydroxyphenethylamine), as well as the 3-O-methylated, deaminated compound HVA, the major final metabolite of DA in humans. Treatment with l-dopa can reduce tissue concentrations of SAMe (122), with uncertain consequences that should be limited by cotreatment with a COMT-inhibitor. COMT acts in both peripheral and cerebral tissues, although the effect of COMT inhibitors to potentiate l-dopa probably occurs mainly in peripheral tissues (17, 198, 219, 220).

Tolcapone 49 (Fig. 9) and entacapone 50 (Fig. 9) are reversible COMT inhibitors. Examination of their chemical structures reveals obvious similarities, and the molecular mechanisms by which these drugs interact with human COMT are proposed to be similar (221). Although the mechanisms of action and pharmacotherapeutic effects are similar for tolcapone and entacapone, they differ with respect to pharmacokinetic properties and adverse effects. Tolcapone has a relatively longer duration of action (8–12 h) and acts both in the brain and the periphery, whereas entacapone has a shorter duration of action (2 h) and acts mostly in the periphery. Some common adverse effects of these agents are predictable and attributable to increased brain DA (e.g., nausea, vivid dreams, confusion, and hallucinations). A potentially fatal adverse effect, however, occurs only with tolcapone—after marketing, three fatal cases of fulminant hepatic failure were observed, leading to its market withdrawal in some countries restriction in the United States to only those patients who have not responded to other therapies and who have appropriate monitoring for hepatic toxicity. The unforeseen hepatotoxicity associated with tolcapone has left entacapone as the only COMT inhibitor in wide clinical use (222), albeit, since the labeling restrictions in 1998, there have been no additional reports of hepatic fatality (223). The mechanism by which liver damage is induced by tolcapone is believed to involve uncoupling of mitochondria oxidative phosphorylation, significantly reducing cellular generation of adenosine triphosphate (224, 225). Additionally, it was shown that tolcapone (but not entacapone) induces cytotoxic pro-oxidant radical formation in hepatocytes (226). Finally, both COMT inhibitors may cause severe diarrhea and produce increased dyskinesias that may require a reduction in the dose of l-dopa (227).

3.2 Agents Acting on Nondopaminergic Systems

3.2.1 Anticholinergic Agents

Cholinergic interneurons in the striatum exert mainly excitatory effects on GABAergic output from the striatum (Fig. 3). Drugs that increase cholinergic neurotransmission (e.g., the cholinesterase inhibitor physostigmine and the direct agonist carbachol) have long been known to aggravate parkinsonism in humans, whereas centrally active muscarinic antagonists (such as the belladonna alkaloids, including atropine), have moderately beneficial effects (17, 228). Accordingly, before the discovery of l-dopa, drug therapy for parkinsonism depended primarily on the limited efficacy of the natural belladonna alkaloids and newer synthetic antimuscarinic alkaloids, as well as antihistamines that also exert central antimuscarinic actions (Fig. 10). Synthetic central anticholinergic agents include benztropine mesylate 51, biperiden 52, the antihistamine diphenhydramine 53, the phenothiazine ethopropazine 54, orphenadrine 55, procyclidine 56, and trihexylphenidyl 57. Such drugs continue to be used to control parkinsonism and other adverse extrapyramidal neurological effects of potent D2-receptor antagonist antipsychotic agents, for which they are quite effective (17, 126).

thumbnail image

Figure 10. Agents with central antimuscarinic activity sometimes used to treat idiopathic or neuroleptic drug-induced parkinsonism.

However, central antimuscarinic agents have limited therapeutic benefit in PD. They also exert a range of undesirable adverse effects because of their blockade of peripheral parasympathetic function and adverse CNS actions. These include dry mouth, impaired visual accommodation, constipation, urinary retention, and tachycardia. Adverse CNS effects include delirium, marked by confusion, memory impairment, and psychotic symptoms. Despite their relatively unfavorable benefit/risk ratio, these agents are still sometimes employed in the treatment of PD in combination with l-dopa, particularly to help control tremor (228).

3.2.2 Adenosine Receptor Antagonists

Adenosine is a nucleoside signaling molecule that acts at four GPCR subtypes, A1, A2A, A2B, and A3. The mRNA for A2A receptor protein is highly concentrated in the striatum, nucleus accumbens, and olfactory tubercle, and colocalizes with D2 receptor mRNA in these brain regions (229). Activation of A2A receptors inhibits GABA release in striatum and reduces GABA-mediated inhibition of striatal medium spiny output neurons (230). Thus, antagonism of A2A receptors is expected to increase GABA-mediated inhibition of the medium spiny output neurons to help compensate for the loss of DA D1 receptor-stimulated GABA release and D2 receptor-mediated inhibition of these neurons in PD (231) (see Fig. 3). Adenosine A2A receptors also oppose the actions of D1 and D2 receptors on gene expression (232) and second-messenger systems and reduce the binding affinity of DA for D2 receptors (233). An A2A antagonist presumably would block these A2A receptor-mediated inhibitory effects on DA neurotransmission and perhaps provide benefit in PD. Activation of A2A receptors also stimulates release of acetylcholine in striatum (234). Because muscarinic acetylcholine receptor antagonists can ameliorate some signs of PD, A2A receptor antagonists may exert additional benefits in PD by reducing striatal cholinergic neurotransmission. As indicated in Section 2.2.3, there is an inverse relationship between the risk of developing PD and the consumption of caffeine, a nonselective antagonist at adenosine A1 and A2 GPCRs (88, 89).

Istradefylline 58 (formerly, KW 6002) (Fig. 11) is a potent and selective antagonist at adenosine A2A receptors that was shown improving motor disability in primate models of PD (235). A recent double-blind, placebo-controlled clinical trial (236) showed that in patients stabilized on l-dopa and other PD drug regimens, istradefylline-treated subjects had significant reductions in motor fluctuations and the drug was, in general, well tolerated (236). It appears istradefylline will be a useful medication in the treatment of PD. Studies with A1 receptor antagonists lag behind, however, there is evidence they reduce parkinsonian-type tremor in rodents (89).

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Figure 11. Other PD drugs acting on nondopaminergic systems.

3.2.3 Serotonin 5-HT1A Agonists

Dysfunction of neurotransmission mediated by 5-hydroxytryptamine (5-HT; serotonin) occurs in the basal ganglia of patients with PD, and excessive serotonergic transmission may contribute to dyskinesias associated with dopaminergic treatments (237). The central and peripheral psychological and physiological effects of 5-HT are mediated by 14 serotonin receptor subtypes grouped into the 5-HT1 –5-HT7 families. The 5-HT1 family consists of five GPCRs subtypes, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F (238). 5-HT1A receptors are expressed presynaptically on 5-HT terminals, where they limit serotonin release as autoreceptors (239). Their activation should decrease 5-HT release and perhaps alleviate dopaminergic dyskinesias in PD (240). Because 5-HT1A receptor stimulation can reverse parkinsonism-like catalepsy induced by haloperidol (241), 5-HT1A receptor activation might also counteract losses of nigrostriatal DA neurotransmission in PD. Moreover, in patients with advanced PD, intact striatal 5-HT terminals are an important site of decarboxylation of exogenous l-dopa to DA. A 5-HT1A agonist might act at striatal serotonergic terminals to limit release of DA produced by l-dopa treatment and released from 5-HT terminals as a “false transmitter.”

Sarizotan 59 (formerly, EMD-128130) (Fig. 11) is an aminomethylchroman derivative that is fairly well characterized regarding its neurobiochemical activity (242). It has very high affinity (Ki ∼ 0.05 nM) at human 5-HT1A receptors at which it is a full-efficacy agonist relative to 5-HT and it is about 10 times more potent. Sarizotan also has appreciable affinity at human DA D2-, D3-, and D4-receptors (Ki ∼ 2,5 nM), though 50 times less than at 5-HT1A receptors. It is a partial agonist at D2 but demonstrates no apparent activation of D3- and D4-receptors. Given by itself to MPTP-lesioned monkeys, sarizotan had no effect on the severity of motor deficits or on beneficial responses to l-dopa, but it reduced l-dopa-induced choreiform dyskinesias by more than 90% (239). The lack of interaction of sarizotan with l-dopa in MPTP-lesioned monkeys is unsupportive of concern that it might limit release of DA from 5-HT terminals (via 5-HT1A activation) or from DA nerve terminals via D2 activation. The beneficial effects of sarizotan in parkinsonian monkeys seem specific to 5-HT1A agonism, in that they were reversed by a selective 5-HT1A antagonist. In PD patients with dyskinesias resulting from l-dopa therapy, adding sarizotan pharmacotherapy produced significant increases in periods of time without dyskinesia and significant reduction in periods of time with troublesome dyskinesias (243). A subsequent clinical study that assessed improvement of dyskinesias gave mixed results, depending on the dyskinesia rating scale that was used, however, the drug proved to be safe and relatively well tolerated (244). A recent study using the MPTP monkey PD model confirmed sarizotan produces a sustained antidyskinetic effect while maintaining l-dopa antiparkinsonian effects (245) suggesting the 5-HT1A agonist field may prove fruitful in PD drug discovery.

3.2.4 Glutamate Antagonists

The dyskinesias associated with l-dopa therapy may involve overactivity of thalamocortical excitatory glutamatergic input to the motor cerebral cortex (Fig. 3). In addition, excessive release of glutamate due to synaptic overactivity is hypothesized to lead to “excitotoxicity,” resulting from excess neuronal Ca++ influx due to opening of N-methyl-D-aspartate (NMDA) ion channel receptors (246), at which glutamate is a coagonist (along with glycine).

The adamantane derivative, amantadine 60 (Fig. 11), and its dimethylated congener, memantine 61 (Fig. 11), are NMDA glutamate receptor antagonists that might provide neuroprotective effects (247). Both have moderately beneficial effects early in PD, can enhance the effects of l-dopa, and perhaps limit the severity of dyskinesias induced by l-dopa therapy (248). Also, memantine has been used as a spasmolytic agent in the treatment of both PD and dementia (249). Amantadine was originally developed as an antiviral agent and its use in PD patients with influenza revealed unexpected improvement in PD symptoms (250). The pKa of this primary amine is 10.8, thus, it exists mainly in the protonated form at physiological pH. Adamantane and memantine, however, apparently can enter the brain because of their lipophilic cage-like structure that may provide resistance to metabolism by oxidative enzymes—these drugs are excreted mostly unchanged in the urine (251, 252). In addition, amantadine has some ability to release DA and norepinephrine from intraneuronal storage sites and to block reuptake of DA, and was initially considered a DA-potentiating agent for use in mild PD (253).

4 Diagnostic Agents for Parkinson's Disease

  1. Top of page
  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References

Even for an experienced clinical neurologist, diagnosis of PD can be difficult to confirm, especially in the early stages of this disease. Signs of PD vary markedly among patients and in the same person over time; disability can fluctuate dramatically, and progression of the disorder is unpredictable. In addition, a number of conditions mimic PD, and vary in their responses to antiparkinson drugs. Given these difficulties, brain imaging techniques are increasingly applied to diagnostic and neuropharmacological studies of brain function in PD patients. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are sensitive methods employed in such studies.

Spatial resolution is greater with PET, but SPECT technology is less expensive and more widely accessible in many clinical settings. In addition, positron-emitting nuclides used in PET imaging have very short half-lives (inline image, 20 min; inline image, 109 min) and usually require an on-site cyclotron for their production. SPECT nuclides have longer half-lives (inline image, 13 h; inline image, 6 h), often can be supplied commercially, and [inline image]-labeled radioligands can be prepared locally as needed. Specifically, quantitative assessment of nigrostriatal presynaptic DA nerve terminal function by PET using [inline image]-labeled 6-fluoro-l-dopa [inline image]dopa) 62 (Fig. 7) has proved useful for the early diagnosis of PD (254).

Additional radioligands recently have been developed for probing DA transporter (DAT) proteins that are highly characteristic gene products of DA neurons and nerve terminals. Cocaine 63 (Fig. 7) binds to the DAT and other monoamine transporters, but limited DAT-specificity of radiolabeled cocaine and rapid hydrolysis at its benzoyl ester function makes it an impractical candidate for use in imaging (255). However, linking the phenyl ring of cocaine directly to the tropane system yields nonhydrolyzable, long-acting phenyltropanes. Such compounds have proved to be potent psychostimulants; some have high affinity and varying selectivity for cerebral DAT, and have been developed as clinically useful radiopharmaceuticals (Fig. 7).

The first such agent was p-[inline image]phenyl-labeled2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane 31 ([inline image]-β -CIT or RTI-55), although this agent requires about 8 h for peak uptake before imaging, greatly limiting its practicability (186, 256). However, the radioiodinated N-3-fluoropropyl analog of β-CIT (N-3-fluoropropyl-2-β-carbomethoxy-3-β -(4-iodophenyl)-tropane) 64, also known as [inline image]FP-CIT or [inline image]ioflupane, has more favorable kinetics for clinical imaging in 1–2 h after injection of the radioligand (257). A radioligand suitable for PET imaging is obtained by replacing the fluorine atom with [inline image] in FP-CIT (258).

Use of the protein vesicular monoamine transporter 2 (VMAT2) radioligand (+)-[inline image]-dihydrotetrabenazine 65 (Fig. 7) (259) as an investigational positron emission tomography radiotracer for DA neurons also has been reported (260). This agent binds to VMAT2, the transporter that moves nerve terminal cytoplasmic DA into synaptic vesicles for storage and subsequent exocytotic release, thus, serving as a biomarker of DA neuronal loss in PD (261, 262).

5 Future Directions

  1. Top of page
  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References

Research related to PD has been directed toward developing more effective and better-tolerated treatments, largely guided by the central role of DA in the pathophysiology of the disorder. Nevertheless, recent research has increasingly included efforts to clarify the pathophysiology of PD more broadly (15). Regarding elucidation of the still-obscure primary cause of PD, emphasis is on understanding the mechanisms of DA neuronal cell death, including apparently genetically programmed death (apoptosis) that certainly involves mitochondria and may converge with hypotheses involving dysfunctional mitochondrial oxidation, neurotoxicants, and genetic mutations (263).

Several gene mutations have been linked to PD but most occur in uncommon familial cases. Thus, genetic testing is not likely to be useful for screening in the general population, where most cases are thought to occur sporadically. Guided by improved understanding of neuroanatomical and neurophysiological abnormalities in PD, there have been important advances in developing novel diagnostic agents for PD. Although neuroimaging is not required to make a diagnosis of PD (5), it may help in early identification of suspected cases. Increasing use of clinical neuroimaging with PET and SPECT techniques using brain-imaging agents to detect losses of DA neurons in PD in vivo, and perhaps application of functional magnetic resonance imaging (fMRI) methods are aiding early diagnosis and should enable monitoring of the progression of the disease. Ability to monitor the progression of PD should also encourage development of novel treatments aimed at slowing the progression of the disease.

Innovative neurosurgical PD treatment methods include application of deep brain stimulation (264). Transplantation of fetal DA neurons into the striatum of PD patients can alleviate motor deficits, however, dyskinesias frequently result and pathological problems develop in the grafted cells such as reduced DA transporter and tyrosine hydroxylase expression (265). Future DA neuronal cell replacement therapy almost certainly will involve use of embryonic stem cells to obtain large quantities of correctly differentiated midbrain DA neurons for transplantation (266).

Finally, the search for improved medicinal agents for the treatment of PD continues, greatly stimulated by the broadening range of leads targeting nondopaminerigc neurotransmission systems discussed above. With regard to DA, adenosine, and serotonin GPCR drug targets in PD, ligands targeting allosteric sites rather than the endogenous ligand binding (orthosteric) site offer the possibility of enhanced target selectivity (due to less conserved amino acid sequence), novel pharmacology, and/or, enhanced tolerance and safety (no intrinsic activity of allosteric ligand, but, it can modulate endogenous agonist activity) (267). These and other novel medicinal chemistry approaches, in light of continued advances in delineating PD primary pathoetiology and recent renewed emphasis on collaboration between the basic and the clinical biomedical research scientists, likely will provide significantly improved symptomatic PD therapy, and perhaps halt or even reverse the associated neuronal degeneration.

Acknowledgments

  1. Top of page
  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References

For reviewing this manuscript, helpful suggestions, and material, we thank Drs. Ludy Shih, Frank Tarazi, and Daniel Tarsy of Harvard Medical School, Boston, MA. We thank the Branfman Family Foundation and acknowledge support by NIH grants MH-068655, MH-081193, DA-023928, Bruce J. Anderson Foundation, and the McLean Private Donors Neuropharmacology Research Fund.

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  2. Introduction
  3. Parkinson's Disease
  4. Parkinson's Disease Pharmacotherapy
  5. Diagnostic Agents for Parkinson's Disease
  6. Future Directions
  7. Acknowledgments
  8. References
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