Mecamylamine (racemate) is a well-known noncompetitive inhibitor of nicotinic acetylcholine receptors. It has previously been shown to have antidepressant effects in appropriate animal models.
TC-5214 (S-(+)-Mecamylamine): A Neuronal Nicotinic Receptor Modulator with Antidepressant Activity
Article first published online: 11 NOV 2008
© 2008 Targacept, Inc. Journal compilation © 2008 Blackwell Publishing Ltd
CNS Neuroscience & Therapeutics
Volume 14, Issue 4, pages 266–277, Winter 2008
How to Cite
Lippiello, P. M., Beaver, J. S., Gatto, G. J., James, J. W., Jordan, K. G., Traina, V. M., Xie, J. and Bencherif, M. (2008), TC-5214 (S-(+)-Mecamylamine): A Neuronal Nicotinic Receptor Modulator with Antidepressant Activity. CNS Neuroscience & Therapeutics, 14: 266–277. doi: 10.1111/j.1755-5949.2008.00054.x
This article demonstrates that TC-5214 (S-(+)-enantiomer of mecamylamine) has distinct and different pharmacological properties from the racemate or the R-(−)-enantiomer that are manifested as greater potency and efficacy in animal models of depression and anxiety and in a greater safety margin.
- Issue published online: 11 NOV 2008
- Article first published online: 11 NOV 2008
Both clinical and preclinical data support a potential therapeutic benefit of modulating the activity of CNS neuronal nicotinic receptors (NNRs) to treat depression and anxiety disorders. Based on the notion that the depressive states involve hypercholinergic tone, we have examined the potential palliative role of NNR antagonism in these disorders, using TC-5214 (S-(+) enantiomer of mecamylamine), a noncompetitive NNR antagonist. TC-5214 demonstrated positive effects in a number of animal models of depression and anxiety. TC-5214 was active in the forced swim test in rats (minimum effective dose (MED) = 3 mg/kg i.p.), a classical depression model. It was also active in the behavioral despair test in mice (0.1–3.0 mg/kg i.p.), another model of depression. In the social interaction paradigm in rats, a model of generalized anxiety disorder (GAD), TC-5214 was active at a dose of 0.05 mg/kg s.c. In the light/dark chamber paradigm in rats, a model of GAD and phobia, TC-5214 was also active at a dose of 0.05 mg/kg s.c. Although TC-5214 shows modest selectivity among NNR subtypes, the antidepressant and anxiolytic effects seen in these studies are likely attributable to antagonist effects at the α4β2 NNRs. This is supported by the observation of similar effects with α4β2-selective partial agonists such as cytisine and with α4β2-selective antagonists such as TC-2216. TC-5214 was well tolerated in acute and chronic toxicity studies in mice, rats, and dogs, showed no mutagenicity and displayed safety pharmacology, pharmacokinetic and metabolic profiles appropriate for therapeutic development. Overall, the results support a novel nicotinic cholinergic antagonist mechanism for antidepressant and anxiolytic effects and highlight the potential of NNR antagonists such as TC-5214 as therapeutics for the treatment of anxiety and depression.