@article{6f6c8bfb2c334ef8a8d3fb470e98c233,
title = "Synthesis and Pharmacology of a Novel μ-δOpioid Receptor Heteromer-Selective Agonist Based on the Carfentanyl Template",
abstract = "In this work, we studied a series of carfentanyl amide-based opioid derivatives targeting the mu opioid receptor (μOR) and the delta opioid receptor (δOR) heteromer as a credible novel target in pain management therapy. We identified a lead compound named MP135 that exhibits high G-protein activity at μ-δheteromers compared to the homomeric δOR or μOR and low β-arrestin2 recruitment activity at all three. Furthermore, MP135 exhibits distinct signaling profile, as compared to the previously identified agonist targeting μ-δheteromers, CYM51010. Pharmacological characterization of MP135 supports the utility of this compound as a molecule that could be developed as an antinociceptive agent similar to morphine in rodents. In vivo characterization reveals that MP135 maintains untoward side effects such as respiratory depression and reward behavior; together, these results suggest that optimization of MP135 is necessary for the development of therapeutics that suppress the classical side effects associated with conventional clinical opioids.",
author = "Abdelfattah Faouzi and Rajendra Uprety and Ivone Gomes and Nicolas Massaly and Keresztes, {Attila I.} and {Le Rouzic}, Valerie and Achla Gupta and Tiffany Zhang and Yoon, {Hye Jean} and Michael Ansonoff and Abdullah Allaoa and Pan, {Ying Xian} and John Pintar and Mor{\'o}n, {Jose A.} and Streicher, {John M.} and Devi, {Lakshmi A.} and Susruta Majumdar",
note = "Funding Information: A.F. acknowledges support from the Phillipe Foundation. S.M. is supported by funds from NIH grants DA045884, DA046487, AA026949, and W81XWH-17-1-0256 (Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program) and start-up funds from Center for Clinical Pharmacology, Washington University and Faculty Research Incentive Funds (FRIF) from St. Louis College of Pharmacy to S.M. This research was funded in part through the NIH/NCI Cancer Center Support grant P30 CA008748. Studies were also supported by NIDA grants: DA042888, DA046714, DA007242, and DA006241 (Y.X.P.); DA041781, DA042499, and DA045463 (J.A.M.); UG3DA047717 and R21DA044509 (J.M.S.); and DA008863 and DA026880 (L.A.D.). Authors would like to thank Satyanarayana Chintala in the Alex Evers Laboratory at Washington University Department of Anesthesiology for helping run HPLCs on all compounds. Publisher Copyright: {\textcopyright} 2020 American Chemical Society. All rights reserved.",
year = "2020",
month = nov,
day = "25",
doi = "10.1021/acs.jmedchem.0c00901",
language = "English",
volume = "63",
pages = "13618--13637",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
number = "22",
}