TY - JOUR
T1 - A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects
AU - Chakraborty, Soumen
AU - DiBerto, Jeffrey F.
AU - Faouzi, Abdelfattah
AU - Bernhard, Sarah M.
AU - Gutridge, Anna M.
AU - Ramsey, Steven
AU - Zhou, Yuchen
AU - Provasi, Davide
AU - Nuthikattu, Nitin
AU - Jilakara, Rahul
AU - Nelson, Melissa N.F.
AU - Asher, Wesley B.
AU - Eans, Shainnel O.
AU - Wilson, Lisa L.
AU - Chintala, Satyanarayana M.
AU - Filizola, Marta
AU - van Rijn, Richard M.
AU - Margolis, Elyssa B.
AU - Roth, Bryan L.
AU - McLaughlin, Jay P.
AU - Che, Tao
AU - Sames, Dalibor
AU - Javitch, Jonathan A.
AU - Majumdar, Susruta
N1 - Funding Information:
S.M. and D.S. is supported by funds from NIH grants DA045884 and DA046487. S.M. is further supported by DA048379. J.A.J. is supported by a grant from the Hope for Depression Research Foundation. M.F. is supported by NIH grants DA034049 and DA045884. Computations were run on resources available through the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880 (to the Icahn School of Medicine at Mount Sinai), as well as the Extreme Science and Engineering Discovery Environment under MCB080077 (to MF), which is supported by National Science Foundation grant number ACI-1548562. R.V.R. is supported by NIH grants AA026949. EBM is supported by funds from the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society
PY - 2021/9/23
Y1 - 2021/9/23
N2 - 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-OCH3group 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-proteinEmax≈ 10%) in cell lines while yet attaining maximal antinociceptionin vivowith reduced opioid liabilities.
AB - 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-OCH3group 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-proteinEmax≈ 10%) in cell lines while yet attaining maximal antinociceptionin vivowith reduced opioid liabilities.
UR - http://www.scopus.com/inward/record.url?scp=85115623107&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c01273
DO - 10.1021/acs.jmedchem.1c01273
M3 - Article
C2 - 34505767
AN - SCOPUS:85115623107
SN - 0022-2623
VL - 64
SP - 13873
EP - 13892
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -