@article{3764e4eb77bf41599772c0c2ebee5431,
title = "A promising chemical series of positive allosteric modulators of the μ-opioid receptor that enhance the antinociceptive efficacy of opioids but not their adverse effects",
abstract = "Positive allosteric modulators (PAMs) of the μ-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.",
author = "Pryce, {Kerri D.} and Kang, {Hye Jin} and Farhana Sakloth and Yongfeng Liu and Susan Khan and Katalin Toth and Abhijeet Kapoor and Andrew Nicolais and Tao Che and Lihuai Qin and Feodora Bertherat and Kaniskan, {H. {\"U}mit} and Jian Jin and Cameron, {Michael D.} and Roth, {Bryan L.} and Venetia Zachariou and Marta Filizola",
note = "Funding Information: The authors would like to thank Dr. Terry Kenakin for his recommendations on the quantification of signaling bias and allosteric parameters, as well as Dr. Davide Provasi for producing Fig. 7 . This work was supported by National Institutes of Health grants to M.F. (DA045473) , V.Z. ( NS086444 , NS111351 , and DA08227 ), and B.L.R. ( 271201800023C–P00001-9999-1 ). Computations were run on resources available through the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880 . Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = sep,
day = "1",
doi = "10.1016/j.neuropharm.2021.108673",
language = "English",
volume = "195",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Ltd.",
}