Peripheral cannabinoid receptor agonists

Generic Names: anandamide (endogenous ligand); tetrahydrocannabinol Proprietary Names: CR701; WIN-55212-2; JWH-133; AM-1231 Drug Class: central- and peripheral-acting analgesic Manufacturer: CR701: Cara Therapeutics, Shelton CT Chemical Structures: see Figure 126.1 Introduction Although cannabinoid drugs have been used recreationally and therapeutically for millennia little was known regarding their sites of activity and mechanisms of action. In recent years the pharmacological and behavioral properties of these molecules have been more thoroughly defined. Development of ligands that preferentially bind to peripheral receptors may offer the promise of effective analgesia without the central nervous system effects of nonselective cannabinoids. Description Delta-9-tetrahydrocanabinol (THC), the active ligand in Cannabis sativa extract, was thought to exert its pharmacological effects by activating cannabinoid receptors in the central nervous system. These receptors were identified in 1988, and endogenous ligands termed endocannabinoids were isolated in 1992. Two major cannabinoid receptor subtypes termed CB₁ and CB₂ have been characterized. Central CB₁ receptors are primarily localized in neocortex and the limbic system, and are responsible for many of the behavioral and analgesic effects of cannabinoid agonists. Peripheral CB₂ receptors and some CB1 subtypes are primarily localized in immune cells such as leukocytes and mast cells, which have been shown to be involved in pain and inflammatory responses. CB₂ receptors are not present in the CNS; however, they are also found in peripheral nerve fibers and are particularly concentrated in injured neural endings.