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J Med Chem. 2015 May 28;58(10):4220-9. doi: 10.1021/acs.jmedchem.5b00007. Epub 2015 May 7.

Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor.

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†Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
‡Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
⊥Department of Structural and Chemical Biology Icahn School of Medicine at Mount Sinai (ISMMS), New York, New York 10029-6574, United States.
#FORMA Therapeutics, Arsenal Street, Suite 100, Watertown, Massachusetts 02472, United States.
∞DiscoveRx Corporation, 42501 Albrae Street, Suite 100, Fremont, California 94538, United States.
×Primity Bio, 3350 Scott Boulevard, Ste 6101, Santa Clara, California 95054, United States.


Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

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