Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3'-carboxamido)morphinan analogues as opioid receptor ligands.
作者： Yunyun Yuan , Saheem A. Zaidi , David L. Stevens , Krista L. Scoggins , Philip D. Mosier
DOI: 10.1016/J.BMC.2015.02.055
关键词:
摘要: 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 aromatic side chain optimal for MOR selectivity. Meanwhile, substitutions 1′- and/or 4′-position isoquinoline ring retained or improved selectivity over kappa while still possessing above 20-fold delta receptor. In contrast, 6′- 7′-position reduced as well efficacy. Among this ligands, compound 11 acted an antagonist when challenged with morphine in warm-water tail immersion produced less significant withdrawal symptoms compared naltrexone morphine-pelleted mice. Compound also antagonized intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies three receptors indicated orientation 6′-nitro group varied significantly different ‘address’ domains played a crucial role observed affinities Collectively, current findings provide valuable insights future development NAQ-based selective ligands.
sci-hub.se 参考文章(64)
Narayanan Eswar, David Eramian, Ben Webb, Min-Yi Shen, Andrej Sali, Protein structure modeling with MODELLER. Methods of Molecular Biology. ,vol. 426, pp. 145- 159 ,(2008) , 10.1007/978-1-60327-058-8_8
S. I. Ortiz-Miranda, G. Dayanithi, V. Coccia, E. E. Custer, S. Alphandery, E. Mazuc, S. Treistman, J. R. Lemos, mu-Opioid receptor modulates peptide release from rat neurohypophysial terminals by inhibiting Ca(2+) influx. Journal of Neuroendocrinology. ,vol. 15, pp. 888- 894 ,(2003) , 10.1046/J.1365-2826.2003.01076.X
Juan A. Ballesteros, Harel Weinstein, [19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors Methods in Neurosciences. ,vol. 25, pp. 366- 428 ,(1995) , 10.1016/S1043-9471(05)80049-7
PS Portoghese, T Reisine, M Hamon, R Raghubir, F Cesselin, BN Dhawan, PB Bradley, International Union of Pharmacology. XII. Classification of opioid receptors Pharmacological Reviews. ,vol. 48, pp. 567- 592 ,(1996)
P S Portoghese, E E Abdelhamid, M Sultana, A E Takemori, Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. Journal of Pharmacology and Experimental Therapeutics. ,vol. 258, pp. 299- 303 ,(1991)
M. Valiev, E.J. Bylaska, N. Govind, K. Kowalski, T.P. Straatsma, H.J.J. Van Dam, D. Wang, J. Nieplocha, E. Apra, T.L. Windus, W.A. de Jong, NWChem: a comprehensive and scalable open-source solution for large scale molecular simulations Computer Physics Communications. ,vol. 181, pp. 1477- 1489 ,(2010) , 10.1016/J.CPC.2010.04.018
Humphrey A. Moynihan, Ian. Derrick, Jillian H. Broadbear, Benjamin M. Greedy, Mario D. Aceto, Louis S. Harris, Lauren C. S. Purington, Mark P. Thomas, James H. Woods, John R. Traynor, Stephen M. Husbands, John W. Lewis, Fumaroylamino-4,5-epoxymorphinans and related opioids with irreversible μ opioid receptor antagonist effects Journal of Medicinal Chemistry. ,vol. 55, pp. 9868- 9874 ,(2012) , 10.1021/JM301096S
Predrag Kukic, Damien Farrell, Lawrence P. McIntosh, Bertrand García-Moreno E., Kristine Steen Jensen, Zigmantas Toleikis, Kaare Teilum, Jens Erik Nielsen, Protein Dielectric Constants Determined from NMR Chemical Shift Perturbations Journal of the American Chemical Society. ,vol. 135, pp. 16968- 16976 ,(2013) , 10.1021/JA406995J
Guo Li, Lindsey C. Aschenbach, Jianyang Chen, Michael P. Cassidy, David L. Stevens, Bichoy H. Gabra, Dana E. Selley, William L. Dewey, Richard B. Westkaemper, Yan Zhang, Design, Synthesis, and Biological Evaluation of 6α- and 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as μ Opioid Receptor Selective Antagonists Journal of Medicinal Chemistry. ,vol. 52, pp. 1416- 1427 ,(2009) , 10.1021/JM801272C
Eduardo R. Butelman, Vadim Yuferov, Mary Jeanne Kreek, κ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. Trends in Neurosciences. ,vol. 35, pp. 587- 596 ,(2012) , 10.1016/J.TINS.2012.05.005