| Literature DB >> 32530286 |
Rakesh H Vekariya1, Wei Lei2, Abhisek Ray1, Surendra K Saini1, Sixue Zhang1, Gabriella Molnar2, Deborah Barlow3, Kelly L Karlage2, Edward J Bilsky2, Karen L Houseknecht3, Tally M Largent-Milnes2, John M Streicher2, Subramaniam Ananthan1.
Abstract
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 δ/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.Entities:
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Year: 2020 PMID： 32530286 PMCID： PMC9521336 DOI： 10.1021/acs.jmedchem.0c00503
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 8.039