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Bioorg Med Chem. 2015 Apr 15;23(8):1701-15. doi: 10.1016/j.bmc.2015.02.055. Epub 2015 Mar 6.

Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan analogues as opioid receptor ligands.

Author information

1
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yyuan@vcu.edu.
2
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
3
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
4
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yzhang2@vcu.edu.

Abstract

A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1'- and/or 4'-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6'- and/or 7'-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca(2+) increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6'-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.

KEYWORDS:

Antagonist; MOR; SAR; Selectivity

PMID:
25783191
PMCID:
PMC4380750
DOI:
10.1016/j.bmc.2015.02.055
[Indexed for MEDLINE]
Free PMC Article

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