Synthesis of 6,14-epoxymorphinan derivatives and their pharmacologies |
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Authors: | Nemoto Toru Yamamoto Naoshi Watanabe Akio Fujii Hideaki Hasebe Ko Nakajima Mayumi Mochizuki Hidenori Nagase Hiroshi |
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Affiliation: | School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. |
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Abstract: | A novel 6,14-epoxymorphinan benzamide derivative (NS22) that was previously reported showed opioid κ receptor agonistic activity and analgesic activity. The unsatisfactory κ selectivity of NS22 led us to synthesize its derivatives to improve the opioid κ receptor selectivity and the agonist activity. In the course of SAR of the various derivatives, 17-benzyl-6,14-epoxymorphinan derivatives (KNT-33, 53, 55, 80, 90, 133) were found to show high selectivities and affinities for the opioid κ receptor. In addition, KNT-33, 53, 55 showed dose-dependent analgesic effects in acetic acid writhing tests. Therefore, 17-benzyl substituents may play an important role for developing κ selectivity. |
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