Structure–Activity\nRelationships and Molecular\nPharmacology of Positive Allosteric Modulators of the Mu-Opioid Receptor

Positive allosteric modulation of the mu-opioid receptor\nis a promising\nstrategy to address the ever-growing problem of acute and chronic\npain management. Positive allosteric modulators (PAMs) of the mu-opioid\nreceptor could be employed to enhance the efficacy of endogenous opioid\npeptides to a degree that provides pain relief without the need for\ntraditional opioid drugs. Alternatively, PAMs might be used to enhance\nthe action of opioid drugs and so provide an opioid-sparing effect,\nallowing for the use of lower doses of opioid agonists and potentially\ndecreasing associated side effects. BMS-986122 (2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl)-sulfonyl]-thiazolidine)\nhas been previously identified as a PAM of the mu-opioid receptor.\nIn the present work, we have designed and synthesized 33 analogs of\nBMS-986122 to explore the structure–activity relationships\nof this scaffold and confirm its allosteric mechanism of action. Among\nseveral newly identified modulators, the most promising compound (<b>14b</b>) had improved activity to increase the in vitro potency\nof the standard mu-opioid agonist DAMGO and showed in vivo activity\nin mice to enhance the antinociceptive action of morphine.