Pharmacology of cannabinoid receptor ligands

Mammalian tissues contain at least two types of cannabinoid receptor, CB1 a nd CB2, both coupled to G proteins. CB1 receptors are expressed mainly by n eurones of the central and peripheral nervous system whereas CB2 receptors occur in certain non-neuronal tissues, particularly in immune cells. The ex istence of endogenous ligands for cannabinoid receptors has also been demon strated. The discovery of this 'endogenous cannabinoid system' has been par alleled by a renewed interest in possible therapeutic applications of canna binoids, for example in the management of pain and in the suppression of mu scle spasticity/spasm associated with multiple sclerosis or spinal cord inj ury. It has also prompted the development of a range of novel cannabinoid r eceptor ligands, including several that show marked selectivity for CB1 or CB2 receptors. This review summarizes current knowledge about the in vitro pharmacological properties of important CB1 and CB2 receptor ligands. Parti cular attention is paid to the binding properties of these ligands, to the efficacies of cannabinoid receptor agonists, as determined using cyclic AMP or [S-35]GTP gamma S binding assays, and to selected examples of how these pharmacological properties can be influenced by chemical structure. The in vitro pharmacological properties of ligands that can potently and selectiv ely oppose the actions of CB1 or CB2 receptor agonists are also described. When administered by themselves, some of these ligands produce effects in c ertain tissue preparations that are opposite in direction to those produced by cannabinoid receptor agonists and the possibility that the ligands prod ucing such 'inverse cannabimimetic effects' are inverse agonists rather tha n pure antagonists is discussed.