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

Burford, Neil T.; Livingston, Kathryn E.; Canals, Meritxell; Ryan, Molly R.; Budenholzer, L.M.L.; Han, Ying; Shang, Yi; Herbst, John J.; OConnell, Jonathan; Banks, Martyn; Zhang, Litao; Filizola, Marta; Bassoni, Daniel L.; Wehrman, Tom S.; Christopoulos, Arthur; Traynor, John R.; Gerritz, Samuel W.; Alt, Andrew

Authors

Neil T. Burford

Kathryn E. Livingston

Molly R. Ryan

L.M.L. Budenholzer

Ying Han

Yi Shang

John J. Herbst

Jonathan OConnell

Martyn Banks

Litao Zhang

Marta Filizola

Daniel L. Bassoni

Tom S. Wehrman

Arthur Christopoulos

John R. Traynor

Samuel W. Gerritz

Andrew Alt



Abstract

© 2015 American Chemical Society. 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.

Journal Article Type Article
Publication Date Apr 22, 2015
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 58
Issue 10
Pages 4220-4229
APA6 Citation Burford, N. T., Livingston, K. E., Canals, M., Ryan, M. R., Budenholzer, L., Han, Y., …Alt, A. (2015). Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor. Journal of Medicinal Chemistry, 58(10), 4220-4229. https://doi.org/10.1021/acs.jmedchem.5b00007
DOI https://doi.org/10.1021/acs.jmedchem.5b00007
Keywords 3,3,6,6 tetramethyl 9 [4 [(2 methylbenzyl)oxy]phenyl] 3,4,5,6,7,9 hexahydro 1h xanthene 1,8(2h) dione; 9 [4 [(2 bromobenzyl)oxy]phenyl] 3,3,6,6 tetramethyl 3,4,5,6,7,9 hexahydro 1h xanthene 1,8(2h) dione; beta arrestin; cyclic AMP; delta opiate receptor;
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