Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the ?-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

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.

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

• Journal Article Type: Article
• Acceptance Date: Jan 2, 2015
• Online Publication Date: Apr 22, 2015
• Publication Date: Apr 22, 2015
• Deposit Date: Jan 17, 2020
• 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
• 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
• Public URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-84930645010&doi=10.1021%2facs.jmedchem.5b00007&partnerID=40&md5=8ad51a430685edc88f7b7b3a0c6ef790