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

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

  • Bioorg Med Chem. 2015 Apr 15;23(8):1701-15. doi: 10.1016/j.bmc.2015.02.055.
Yunyun Yuan 1,  Saheem A Zaidi 2,  David L Stevens 3,  Krista L Scoggins 3,  Philip D Mosier 2,  Glen E Kellogg 2,  William L Dewey 3,  Dana E Selley 3,  Yan Zhang 4
Affiliations

Affiliations

  • 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.
PMID: 25783191 DOI: 10.1016/j.bmc.2015.02.055
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.

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