Allosteric modulation

Allosteric modulation is the regulation of a receptor's response to its orthosteric (primary) ligand by a second molecule binding at a distinct ("allosteric") site. Positive allosteric modulators (PAMs) increase, and negative allosteric modulators (NAMs) decrease, orthosteric ligand potency or efficacy. At CB1, characterized allosteric ligands include the NAMs ORG27569 and PSNCBAM-1, and — critically for cannabis pharmacology — CBD, which acts as a CB1 NAM (Laprairie et al., 2015, British Journal of Pharmacology 172:4790). This finding provides a molecular basis for CBD's ability to blunt some of the adverse effects of THC (anxiety, tachycardia) without itself producing intoxication. Allosteric approaches are attractive for drug discovery because they preserve temporal and spatial patterns of endogenous signaling rather than overriding them. → See also: CBD, CB1 receptor, THC.