Abstract ID 23842

Poster Board 565

Mu-opioid receptor agonists are the gold standard for pain treatment. While efficacious for moderate to severe pain, these drugs are associated with serious adverse effects including abuse liability and respiratory depression. One emerging strategy for safer pain treatments is the development of positive allosteric modulators (PAMs) of the mu-opioid receptor (mu-PAMs). Mu-PAMs can enhance analgesia by increasing the activity of endogenous neurotransmitters released during pain states. Because mu-PAMs do not activate MOR in the absence of an orthosteric agonist and the promoting effects on endogenous opioids are localized and temporal, this allosteric strategy holds the promise of analgesia with fewer side effects. Previous work has identified one molecule, BMS-986122 (Figure 1), that enhances the antinociceptive effects of endogenous opioids with a reduced ability to cause constipation, respiratory depression, and reward. However, BMS-986122 is weak with an affinity of 5mM for the mu-opioid receptor, and we do not know how the compound interacts with the receptor. Hence, the presented research aimed to explore structure-activity relationships (SAR) of the BMS986122 scaffold for the design of more potent compounds. Derivatives of BMS-986122 were synthesized and fully characterized (purity >95%). The potency and efficacy of the compounds were determined by their ability to shift the dose-response curve of the standard mu-opioid agonist DAMGO using b-arrestin recruitment and GTPg35S binding assays. By altering the substitution patterns on the aromatic rings and replacing the heterocyclic core (Figure 1) we were able to identify compounds that had no effect on their own but shifted the concentration-response curve for DAMGO up to 35-fold. There was only a minor difference between individual enantiomers (*). Our study has generated a SAR framework of BMS986122, which will facilitate the understanding of the allosteric pharmacophore and the design of better mu-PAMs.

Support/Funding Information: R37 DA039997⇓

Structure of BMS986122.