| Literature DB >> 34505767 |
Soumen Chakraborty1,2, Jeffrey F DiBerto3, Abdelfattah Faouzi1,2, Sarah M Bernhard1,2, Anna M Gutridge4, Steven Ramsey5, Yuchen Zhou5, Davide Provasi5, Nitin Nuthikattu1,2, Rahul Jilakara1,2, Melissa N F Nelson6, Wesley B Asher6, Shainnel O Eans7, Lisa L Wilson7, Satyanarayana M Chintala2, Marta Filizola5, Richard M van Rijn4, Elyssa B Margolis8, Bryan L Roth3, Jay P McLaughlin7, Tao Che1,2,3, Dalibor Sames9, Jonathan A Javitch6, Susruta Majumdar1,2.
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.Entities:
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Year: 2021 PMID： 34505767 PMCID： PMC8530377 DOI： 10.1021/acs.jmedchem.1c01273
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039