Allostery at opioid receptors: modulation with small molecule ligands.
Opioid receptors are 7-transmembrane domain receptors that couple to heterotrimeric G proteins. The endogenous ligands for opioid receptors are peptides which bind to the orthosteric site on the receptors. The μ-opioid receptor is the target for opioid analgesics, while the δ-opioid receptor has been suggested as a target for pain management, migraine and depression. Similarly, κ-opioid receptors are involved in pain and depression and nociceptin receptors in pain and mood behaviours. However, exogenous orthosteric ligands for opioid receptors cause a myriad of on-target side effects. Recently, selective allosteric ligands for μ- and δ-opioid receptors have been described. These compounds bind to a site on the receptor distinct from the orthosteric site. Occupation of this allosteric site leads to modulation of orthosteric ligand binding affinity and/or efficacy. Allosteric modulators may be positive, negative or silent (neutral) (PAMs, NAMs or SAMs respectively). PAMs may have in vivo activity by enhancing the activity of exogenous drugs or endogenous opioid peptides. Enhancing endogenous opioid peptide activity maintains the temporal and spatial distribution of these molecules but improves, and potentially qualitatively changes, activity at their cognate receptors which could limit side effects compared with traditional opioid drugs. In this review, we describe the rationale and promise for the development of allosteric modulators for opioid receptors, the discovery of selective allosteric modulators, the identification of potential allosteric sites on opioid receptors and the mode of action of the modulators.