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 - 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 -