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

2021; American Chemical Society; Volume: 64; Issue: 18 Linguagem: Inglês

10.1021/acs.jmedchem.1c01273

1520-4804

Soumen Chakraborty, Jeffrey F. DiBerto, Abdelfattah Faouzi, Sarah M. Bernhard, Anna M. Gutridge, Steven Ramsey, Yuchen Zhou, Davide Provasi, Nitin Nuthikattu, Rahul Jilakara, Melissa Nelson, Wesley B. Asher, Shainnel O. Eans, Lisa Wilson, Satyanarayana M. Chintala, Marta Filizola, Richard M. van Rijn, Elyssa B. Margolis, Bryan L. Roth, Jay P. McLaughlin, Tao Che, Dalibor Sameš, Jonathan A. Javitch, Susruta Majumdar,

Chemical synthesis and alkaloids

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.