TY - JOUR
T1 - Synthesis and Structure-Activity Relationships of 5′-Aryl-14-alkoxypyridomorphinans
T2 - Identification of a μ Opioid Receptor Agonist/δOpioid Receptor Antagonist Ligand with Systemic Antinociceptive Activity and Diminished Opioid Side Effects
AU - Vekariya, Rakesh H.
AU - Lei, Wei
AU - Ray, Abhisek
AU - Saini, Surendra K.
AU - Zhang, Sixue
AU - Molnar, Gabriella
AU - Barlow, Deborah
AU - Karlage, Kelly L.
AU - Bilsky, Edward J.
AU - Houseknecht, Karen L.
AU - Largent-Milnes, Tally M.
AU - Streicher, John M.
AU - Ananthan, Subramaniam
N1 - Funding Information:
The authors wish to thank Dr. Judith V. Hobrath for performing initial computational modeling studies. We thank Dr. Donghui Bao and Dr. Robert Deimler for their help with analytical and spectral data collection. We are grateful to Dr. Corinne E. Augelli-Szafran and Dr. Mark J. Suto for their encouragement, valuable comments, and suggestions during the course of this work. This study was supported by a research grant from the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH) under award number R01DA038635. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/7/23
Y1 - 2020/7/23
N2 - We previously identified a pyridomorphinan (6, SRI-22138) possessing a 4-chlorophenyl substituent at the 5′-position on the pyridine and a 3-phenylpropoxy at the 14-position of the morphinan as a mixed μ opioid receptor (MOR) agonist and /κ opioid receptor (DOR/KOR) antagonist with potent antinociceptive activity and diminished tolerance and dependence in rodents. Structural variations at the 5′- and 14-positions of this molecule gave insights into the structure-activity relationships for binding and functional activity. Subtle structural changes exerted significant influence, particularly on the ability of the compounds to function as agonists at the MOR. In vivo evaluation identified compound 20 (SRI-39067) as a MOR agonist/DOR antagonist that produced systemically active potent antinociceptive activity in tail-flick assay in mice, with diminished tolerance, dependence/withdrawal, reward liability, and respiratory depression versus morphine. These results support the hypothesis that mixed MOR agonist/DOR antagonist ligands may emerge as novel opioid analgesics with reduced side effects.
AB - We previously identified a pyridomorphinan (6, SRI-22138) possessing a 4-chlorophenyl substituent at the 5′-position on the pyridine and a 3-phenylpropoxy at the 14-position of the morphinan as a mixed μ opioid receptor (MOR) agonist and /κ opioid receptor (DOR/KOR) antagonist with potent antinociceptive activity and diminished tolerance and dependence in rodents. Structural variations at the 5′- and 14-positions of this molecule gave insights into the structure-activity relationships for binding and functional activity. Subtle structural changes exerted significant influence, particularly on the ability of the compounds to function as agonists at the MOR. In vivo evaluation identified compound 20 (SRI-39067) as a MOR agonist/DOR antagonist that produced systemically active potent antinociceptive activity in tail-flick assay in mice, with diminished tolerance, dependence/withdrawal, reward liability, and respiratory depression versus morphine. These results support the hypothesis that mixed MOR agonist/DOR antagonist ligands may emerge as novel opioid analgesics with reduced side effects.
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U2 - 10.1021/acs.jmedchem.0c00503
DO - 10.1021/acs.jmedchem.0c00503
M3 - Article
C2 - 32530286
AN - SCOPUS:85088610185
VL - 63
SP - 7663
EP - 7694
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -