Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3, 14β-dihydroxy-4, 5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands. Issue 8 (15th April 2015)

• Record Type: Journal Article
• Authors: Yuan, Yunyun; Zaidi, Saheem A.; Stevens, David L.; Scoggins, Krista L.; Mosier, Philip D.; Kellogg, Glen E.; Dewey, William L.; Selley, Dana E.; Zhang, Yan
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 8(2015)
• Page Start: 1701
• Page End: 1715
• Publication Date: 2015-04-15
• Subjects: cAMP cyclic adenosine monophosphate -- CHO Chinese hamster ovary -- DAMGO [d-Ala2-MePhe4-Gly(ol)5]enkephalin -- DFT density functional theory -- DOR delta opioid receptor -- DPN diprenorphine -- EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide -- GIRK G protein-gated inwardly rectifying K+ -- GPCR G protein-coupled receptor -- HOBt hydrobenzotriazole -- KOR kappa opioid receptor -- MD molecular dynamics -- MOR mu opioid receptor -- NTX naltrexone -- NTI naltrindole -- NAQ 17-cyclopropylmethyl-3, 14β-dihydroxy-4, 5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan -- NAMD NAnoscale Molecular Dynamics program -- NCQ 17-cyclopropylmethyl-3, 14β-dihydroxy-4, 5α-epoxy-6α-(1-chloro-4-methoxyisoquinoline-3-carboxamido)morphinan -- NNQ 17-cyclopropylmethyl-3, 14β-dihydroxy-4, 5α-epoxy-6α-(6-nitroisoquinoline-3-carboxamido)morphinan -- PME Particle Mesh Ewald -- OPM Orientations of Proteins in Membranes -- SAR structure–activity relationship -- TFF tripos force field -- VGCC voltage-gated Ca2+ channels; MOR -- Antagonist -- SAR -- Selectivity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.02.055
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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, compound11 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. Compound11 also antagonized the intracellular Ca 2+ increase induced by DAMGO. Molecular dynamics simulation studies of11 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.