Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond

ABSTRACT

A major finding—that (–)-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is largely responsible for the psychotropic effects of cannabis—prompted research in the 1970s and 1980s that led to the discovery that this plant cannabinoid acts through at least two types of cannabinoid receptor, CB₁ and CB₂, and that Δ⁹-THC and other compounds that target either or both of these receptors as agonists or antagonists have important therapeutic applications. It also led to the discovery that mammalian tissues can themselves synthesize and release agonists for cannabinoid receptors, the first of these to be discovered being arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol. These ‘endocannabinoids’ are released onto their receptors in a manner that appears to maintain homeostasis within the central nervous system and sometimes either to oppose or to mediate or exacerbate the unwanted effects of certain disorders. This review provides an overview of the pharmacology of cannabinoid receptors and their ligands. It also describes actual and potential clinical uses both for cannabinoid receptor agonists and antagonists and for compounds that affect the activation of cannabinoid receptors less directly, for example by inhibiting the enzymatic hydrolysis of endocannabinoids following their release.