2. Academic Validation
  3. Synthesis and Pharmacology of a Morphinan-Derived Dual Mu-Kappa Opioid Receptor Agonist Analgesic

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

  • ACS Chem Neurosci. 2025 Jul 16;16(14):2714-2737. doi: 10.1021/acschemneuro.5c00312.
Balazs R Varga 1 2,  Rajendra Uprety 3,  Barnali Paul 1 2,  Alexis Knoll 1,  Nokomis Ramos-Gonzalez 1 2,  Kevin Appourchaux 1 2,  Tori Taylor 1 2 4,  Bengisu Turgutalp 1 2,  Ryosuke Shinouchi 5,  Shainnel O Eans 5,  Ashai K Williams 5,  Steven G Vasquez-Grinnell 3,  Saheem Zaidi 6,  Antonina L Nazarova 6,  Andras Varadi 3,  Valerie Le Rouzic 3,  Taylor G Brown 7,  Shani Martinez 7,  Michael Ansonoff 8,  Rebecca Notis Dardashti 3,  Amanda Hunkele 3,  Joan Subrath 3,  Matthew Welch 1 2,  Jin Xu 3,  Grace C Rossi 7,  John Pintar 8,  Gavril W Pasternak 3,  Vsevolod Katritch 6,  Jay P McLaughlin 5,  Ying Xian Pan 3 9 10,  Susruta Majumdar 1 2 3
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, Washington University School of Medicine and University of Health Sciences & Pharmacy at St Louis, St Louis, Missouri 63110-1010, United States.
  • 2 Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St Louis, Missouri 63110-1010, United States.
  • 3 Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065-6007, United States.
  • 4 Department of Psychological and Brain Sciences, Washington University, St Louis, St Louis, Missouri 63130-4899, United States.
  • 5 Department of Pharmacodynamics, University of Florida; Gainesville, Florida 32610, United States.
  • 6 Department of Quantitative and Computational Biology, Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089-0001, United States.
  • 7 Long Island University, Post Campus, Brookville, New York 11201-5301, United States.
  • 8 Department of Neuroscience and Cell Biology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08901-1962, United States.
  • 9 Department of Anesthesiology, New Jersey Medical School, Newark, New Jersey 07103, United States.
  • 10 Rutgers Addiction Research Center, Brain Health Institute, Rutgers University/Rutgers Biomedical and Health Sciences, Piscataway, New Jersey 07103, United States.
PMID: 40566691 DOI: 10.1021/acschemneuro.5c00312
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.

Keywords

biased agonism; mice; opioids; partial agonism.

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