Allosterism and cannabinoid CB1 receptors: the shape of things to come

In 2005, the first evidence was obtained that the cannabinoid CB1 receptor contains an allosteric binding site. The site can be recogni zed by synthetic small molecules, which display a markedly divergent effect on orthosteric ligand affinity versus efficacy; these small molecules are allosteric enhancers of agonist binding affinity and allosteric inhibitors of agonist signalling efficacy. Allosteric modulation heralds a new approach to the manipulation of the endocannabinoid system for therapeutic benefit; it promises to augment the existing portfolio of selective direct agonists, competitive antagonists and enzyme inhibitors.