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
Volume: 16
Issue: 4
ISSN: 1948-7193
Publisher: American Chemical Society  
Publication status: Published
Date Published: 2025-07-16
Online Publication Date: 2025-01-01
Start Page: 2714
End Page: 2737
Language: English
DOI: 10.1021/acschemneuro.5c00312
PUBMED: 40566691
PROVIDER: scopus
PMCID: PMC12288146
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus
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MSK Authors
  1. Yingxian Pan
    133 Pan
  2. Gavril W Pasternak
    415 Pasternak
  3. Joan Jo-Wen Subrath
    10 Subrath
  4. Andras Varadi
    14 Varadi
  5. Paula   Notis
    4 Notis
  6. Jin   Xu
    61 Xu
  7. Amanda Joy Hunkele
    18 Hunkele
  8. Rajendra Uprety
    17 Uprety