title: Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor.
abstract: 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.
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Neil T
authors.initials: NT
authors.lastname: Burford
authors.affiliation: ‡Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Livingston
authors.forename: Meritxell
authors.initials: M
authors.lastname: Canals
authors.forename: Molly R
authors.initials: MR
authors.lastname: Ryan
authors.forename: Lauren M L
authors.initials: LM
authors.lastname: Budenholzer
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.affiliation: ⊥Department of Structural and Chemical Biology Icahn School of Medicine at Mount Sinai (ISMMS), New York, New York 10029-6574, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shang
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Herbst
authors.affiliation: #FORMA Therapeutics, Arsenal Street, Suite 100, Watertown, Massachusetts 02472, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Martyn
authors.initials: M
authors.lastname: Banks
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: ⊥Department of Structural and Chemical Biology Icahn School of Medicine at Mount Sinai (ISMMS), New York, New York 10029-6574, United States.
authors.forename: Marta
authors.initials: M
authors.lastname: Filizola
authors.affiliation: ∞DiscoveRx Corporation, 42501 Albrae Street, Suite 100, Fremont, California 94538, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Bassoni
authors.affiliation: ×Primity Bio, 3350 Scott Boulevard, Ste 6101, Santa Clara, California 95054, United States.
authors.forename: Tom S
authors.initials: TS
authors.lastname: Wehrman
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.affiliation: ‡Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Gerritz
authors.affiliation: †Research and Development/Discovery, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D003412:Cricetulus; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004743:Enkephalin, Leucine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D011804:Quinolines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D001549:Benzamides; D010879:Piperazines; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; D000071557:beta-Arrestins; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D004743:Enkephalin, Leucine; D048049:Extracellular Signal-Regulated MAP Kinases