Synthesis and Pharmacology of a Morphinan-Derived Dual Mu-Kappa Opioid Receptor Agonist Analgesic Journal Article

   


Authors: Varga, B. R.; Uprety, R.; Paul, B.; Knoll, A.; Ramos-Gonzalez, N.; Appourchaux, K.; Taylor, T.; Turgutalp, B.; Shinouchi, R.; Eans, S. O.; Williams, A. K.; Vasquez-Grinnell, S. G.; Zaidi, S.; Nazarova, A. L.; Varadi, A.; Le Rouzic, V.; Brown, T. G.; Martinez, S.; Ansonoff, M.; Dardashti, R. N.; Hunkele, A.; Subrath, J.; Welch, M.; Xu, J.; Rossi, G. C.; Pintar, J.; Pasternak, G. W.; Katritch, V.; McLaughlin, J. P.; Pan, Y. X.; Majumdar, S.
Article Title: Synthesis and Pharmacology of a Morphinan-Derived Dual Mu-Kappa Opioid Receptor Agonist Analgesic
Abstract: We present the synthesis and pharmacological characterization of 3′-iodobenzoylamido epoxymorphinans, with a saturated ring C and devoid of 14-OH, based on a dihydronormorphine backbone with various N-17 alkyl substitutions. All synthesized compounds were characterized pharmacologically in radioligand binding assays, [35S] GTPγS functional assays, and for antinociception in mice. Among these analogues, MP1202, a pan-opioid receptor analogue, was characterized further in β-arrestin1/2 studies, G-protein recruitment and Gα-subtype profiling, as well as by evaluation of opioid-mediated effects in mice. MP1202 exhibits potent antinociceptive effects in mice without causing typical opioid side effects, such as respiratory depression and physical dependence. However, it displays conditioned place preference and aversion behaviors similar to those of classical mu and kappa agonists. © 2025 American Chemical Society.
Keywords: mouse; animal; metabolism; animals; mice; mice, inbred c57bl; c57bl mouse; chemistry; narcotic analgesic agent; opioids; analgesics, opioid; mu opiate receptor; receptors, opioid, mu; synthesis; guanosine 5'-o-(3-thiotriphosphate); kappa opiate receptor; partial agonism; morphinan derivative; guanosine 5' o (3 thiotriphosphate); humans; human; male; biased agonism; receptors, opioid, kappa; morphinans
Journal Title: ACS Chemical Neuroscience
ISSN: 1948-7193
Publisher: American Chemical Society  
Publication status: Online ahead of print
Date Published: 2025-01-01
Online Publication Date: 2025-01-01
Language: English
DOI: 10.1021/acschemneuro.5c00312
PUBMED: 40566691
PROVIDER: scopus
PMCID: PMC12288146
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-105009042138&doi=10.1021%2facschemneuro.5c00312&partnerID=40&md5=bde2c13e4bcc8e6e9be165c20d4b7757
Notes: Article -- Source: Scopus
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