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J Chem Inf Model. 2015 Sep 28;55(9):1836-43. doi: 10.1021/acs.jcim.5b00388. Epub 2015 Sep 15.

Ligand-Based Discovery of a New Scaffold for Allosteric Modulation of the μ-Opioid Receptor.

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Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Discovery, Bristol-Myers Squibb Company , Wallingford, Connecticut 06492, United States.
Department of Pharmacology, University of Michigan Medical School , Ann Arbor, Michigan 48109, United States.
Department of Molecular Biophysics and Biochemistry, Yale University , New Haven, Connecticut 06520, United States.


With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators of the opioid receptors. In the past two years, the first chemotypes of positive or silent allosteric modulators (PAMs or SAMs, respectively) of μ- and δ-opioid receptor types have been reported in the literature. During a structure-guided lead optimization campaign with μ-PAMs BMS-986121 and BMS-986122 as starting compounds, we discovered a new chemotype that was confirmed to display μ-PAM or μ-SAM activity depending on the specific substitutions as assessed by endomorphin-1-stimulated β-arrestin2 recruitment assays in Chinese Hamster Ovary (CHO)-μ PathHunter cells. The most active μ-PAM of this series was analyzed further in competition binding and G-protein activation assays to understand its effects on ligand binding and to investigate the nature of its probe dependence.

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