2. Academic Validation
  3. A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

  • J Med Chem. 2021 Sep 23;64(18):13873-13892. doi: 10.1021/acs.jmedchem.1c01273.
Soumen Chakraborty 1 2,  Jeffrey F DiBerto 3,  Abdelfattah Faouzi 1 2,  Sarah M Bernhard 1 2,  Anna M Gutridge 4,  Steven Ramsey 5,  Yuchen Zhou 5,  Davide Provasi 5,  Nitin Nuthikattu 1 2,  Rahul Jilakara 1 2,  Melissa N F Nelson 6,  Wesley B Asher 6,  Shainnel O Eans 7,  Lisa L Wilson 7,  Satyanarayana M Chintala 2,  Marta Filizola 5,  Richard M van Rijn 4,  Elyssa B Margolis 8,  Bryan L Roth 3,  Jay P McLaughlin 7,  Tao Che 1 2 3,  Dalibor Sames 9,  Jonathan A Javitch 6,  Susruta Majumdar 1 2
Affiliations

Affiliations

  • 1 Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 2 Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, United States.
  • 4 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
  • 5 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 6 Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United States.
  • 7 Department of Pharmacodynamics, University of Florida, Gainesville, Florida 032610, United States.
  • 8 Department of Neurology, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California 94158, United States.
  • 9 Department of Chemistry, Columbia University, New York 10027, United States.
PMID: 34505767 DOI: 10.1021/acs.jmedchem.1c01273
Abstract

Mitragynine and 7-hydroxymitragynine (7OH) are the major Alkaloids mediating the biological actions of the psychoactive plant kratom. To investigate the structure-activity relationships of mitragynine/7OH templates, we diversified the aromatic ring of the indole at the C9, C10, and C12 positions and investigated their G-protein and Arrestin signaling mediated by mu opioid receptors (MOR). Three synthesized lead C9 analogs replacing the 9-OCH3 group with phenyl (4), methyl (5), or 3'-furanyl [6 (SC13)] substituents demonstrated partial agonism with a lower efficacy than DAMGO or morphine in heterologous G-protein assays and synaptic physiology. In assays limiting MOR reserve, the G-protein efficacy of all three was comparable to buprenorphine. 6 (SC13) showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning in mice. These results suggest the possibility of activating MOR minimally (G-protein Emax ≈ 10%) in cell lines while yet attaining maximal antinociception in vivo with reduced opioid liabilities.

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