Structure–Activity Relationships and Molecular Pharmacology of Positive Allosteric Modulators of the Mu-Opioid Receptor

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