Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development

This review highlights some important advances that have taken place in can nabinoid research over the last four years. It focuses on novel ligands tha t are of interest either as experimental tools or as lead compounds for the rapeutic agents and possible clinical applications for some of these ligand s. The molecular targets for these compounds are various components of the system of endogenous cannabinoids (endocannabinoids) and receptors that tog ether constitute the 'endocannabinoid system'. These are CB1 cannabinoid re ceptors that are present mainly on central and peripheral neurones, CB2 can nabinoid receptors that are expressed predominantly by immune cells, the bi ochemical mechanisms responsible for the tissue uptake or metabolism of end ocannabinoids and vanilloid receptors. Other cannabinoid receptor types may also exist. Recently developed ligands include potent and selective agonis ts for CB1 and CB2 receptors, a potent CB2-selective antagonist/inverse ago nist and inhibitors of endocannabinoid uptake or metabolism. Future researc h should be directed at characterising the endocannabinoid system more comp letely and at obtaining more conclusive clinical data about the possible be neficial effects of cannabinoids as well as their adverse effects. There is also a need for improved cannabinoid formulations/modes of administration in the clinic and advances in this area should be facilitated by the recent development of a potent water-soluble CB1/CB2 receptor agonist. A growing number of strategies for separating sought-after therapeutic effects of can nabinoid receptor agonists from the unwanted consequences of CB1 receptor a ctivation are now emerging and these are discussed at the end of this revie w.