Synthesis and evaluation of novel opioid ligands with a C-homomorphinan skeleton |
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| Institution: | 1. Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan;2. Department of Instrumental Analysis, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan;1. Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada;2. Division of Pharmacology, Mekai University School of Dentistry, Saitama 350-0238, Japan;3. Rega Institute of Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium;4. Faculty of Pharmaceutical Sciences, Matsuyama University, Matsuyama, Ehime 790-8578, Japan;1. Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima, Japan;2. Department of Neurology, Hiroshima City Asa Hospital, Hiroshima, Japan;1. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, P.O. Box 370, H-1445 Budapest, Hungary;2. Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62., H- 6726 Szeged, Hungary;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Semmelweis University, H?gyes Endre u., 9., H-1092 Budapest, Hungary |
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| Abstract: | As the reports about C-homomorphinans with the seven-membered C-ring are much fewer than those of morphinan derivatives with a six-membered C-ring, we attempted to synthesize C-homomorphinan derivatives and to evaluate their opioid activities. C-Homomorphinan 5 showed sufficient binding affinities to the opioid receptors. C-Homomorphinan derivatives possessing the δ address moiety such as indole (NTI-type), quinoline, or benzylidene (BNTX-type) functionalities showed the strongest binding affinities for the δ receptor among the three types of opioid receptors, which indicated that the C-homomorphinan skeleton sufficiently functions as a message-part in the ligand. Although NTI-type compound 8 and quinoline compound 9 with C-homomorphinan scaffold exhibited lower affinities and selectivities for the δ receptor than the corresponding morphinan derivatives did, both the binding affinity and selectivity for the δ receptor of BNTX-type compound 12 with a seven-membered C-ring were improved compared with the corresponding compounds with a six-membered C-ring including BNTX itself. BNTX-Type compound 12 was the most selective δ receptor antagonist among the tested compounds. |
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| Keywords: | Opioid δ Opioid receptor |
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