Targeting the endocannabinoid system: Structural determinants and molecular mechanism of allosteric modulation.

Although drugs targeting the orthosteric binding site of cannabinoid receptors (CBRs) have several therapeutic effects on human physiological and pathological conditions, they can also cause serious adverse effects. Only a few orthosteric ligands have successfully passed clinical trials. Recently, allosteric modulation has become a novel option for drug discovery, with fewer adverse effects and the potential to avoid drug overdose. In this review, we highlight novel findings related to the drug discovery of allosteric modulators (AMs) targeting CBRs. We summarize newly synthesized AMs and the reported/predicted allosteric binding sites. We also discuss the structural determinants of the AMs binding as well as the molecular mechanism of CBR allostery.