Current Cannabinoid Receptor Nomenclature and Pharmacological Principles

The CB1 and CB2 cannabinoid receptors are members of the G protein-coupled receptor (GPCR) family that were isolated more than 20 years ago. CB1 and CB2 mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive ingredient in marijuana and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonyl glycerol. The discovery of additional sites of action for endocannabinoids as well as synthetic cannabinoid compounds suggests the existence of additional cannabinoid receptors. We review this evidence, as well as the current nomenclature for classifying a target as a cannabinoid receptor. We discuss basic pharmacological definitions and principles in order to place in context the mechanisms underlying cannabinoid receptor activation. Constitutive (agonist independent) activity and allosterism are observed with cannabinoid receptors. Allosteric modulation of cannabinoid receptors may usher in new classes of medicinal compounds capable of enhancing signals generated by endocannabinoids. Natural polymorphisms and alternative splice variants may also contribute to the pharmacological diversity of the cannabinoid receptors. Thus, each of the cannabinoid receptors is able to recognize multiple classes of compounds and produce an array of distinct downstream effects. However, many challenges await the field, including the classification of other GPCRs (i.e., GPR18 and GPR55) as bona fide cannabinoid receptors and developing strategies to target receptor conformations for harnessing specific pharmacological responses. The basic biology of the endocannabinoid system will continue to be revealed by ongoing investigations, and progress will partially depend upon the development of technologies that can assimilate current research trends and theories.