title: Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan analogues as opioid receptor ligands.
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.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yyuan@vcu.edu.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Saheem A
authors.initials: SA
authors.lastname: Zaidi
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Stevens
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Scoggins
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Dewey
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, VA 23298, USA.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Selley
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yzhang2@vcu.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D009019:Morphinans / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D009021:Morphine Dependence / Q000188:drug therapy / Q000378:metabolism; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C587362:17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6alpha-(isoquinoline-3'-carboxamido)morphinan; D007546:Isoquinolines; D008024:Ligands; D009019:Morphinans; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu
keywords: Antagonist; MOR; SAR; Selectivity