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J Med Chem. 2016 May 26;59(10):4985-98. doi: 10.1021/acs.jmedchem.6b00308. Epub 2016 May 16.

Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands.

Author information

1
Interdepartmental Program in Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
2
Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
3
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.

Abstract

N-Acetylation of the tetrahydroquinoline (THQ) core of a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.

PMID:
27148755
PMCID:
PMC4885601
DOI:
10.1021/acs.jmedchem.6b00308
[Indexed for MEDLINE]
Free PMC Article

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