- 著者
- Takanobu KUROITA Masamitsu SAKAMORI Takeshi KAWAKITA
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.44, no.4, pp.756-764, 1996-04-15 (Released:2008-03-31)
- 参考文献数
- 24
- 被引用文献数
- 25 31
Several 3-substituted 5-chloro-2-methoxybenzamides were synthesized and evaluated for serotonin-3 (5-HT-3) receptor binding affinity. The 5-HT3 receptor antagonistic activity of zacopride, a representative 5-HT3 receptor antagonist, was unchanged by the replacement of the 4-amino substituent on the aromaitc moiety by a 3-dimethyl-amino substituent. This finding prompted a structural modification of azasetron, another 5-HT3 receptor antagonist. Consequently, a new series of 3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxamides was obtaiend and these compounds were found to be more potent than 3, 4-dihydro-3-oxo-2H-1, 4-bvenzoxazine-8-carboxamids. In particular, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-3, 4-dihydro-4-methyl-2H-1, 4-benzoxazine-8-carboxaminde showed a high affinity for 5-HT3 receptors (Ki=0.051 nM) and especially potent antagonistic activity against the von Bezold-Jarisch reflex (ED50=0.089 μg/kg i.v.) in rats.
- 著者
- Takanobu KUROITA Nobuhiro MARUBAYASHI Mitsuharu SANO Kouji KANZAKI Kenichi INABA Takeshi KAWAKITA
- 出版者
- The Pharmaceutical Society of Japan
- 雑誌
- Chemical and Pharmaceutical Bulletin (ISSN:00092363)
- 巻号頁・発行日
- vol.44, no.11, pp.2051-2060, 1996-11-15 (Released:2008-03-31)
- 参考文献数
- 29
- 被引用文献数
- 21 29
A series of 3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activities by means of assays of 5-HT3 receptor binding and the ability to antagonize the von Bezold-Jarisch reflex in rats. Replacement of the 1, 4-benzoxazine ring with a 1, 4-benzthiazine ring or seven-membered ring (i.e., 1, 5-benzoxepine or 1, 5-benzthiepine) resulted in decreased affinity for 5-HT3 receptor. Introduction of substituents at the 2 position of the 1, 4-benzoxazine ring increased the antagonistic activities (dimethyl>methyl>dihydro>phenyl). The compounds bearing a 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety as the basic part of 3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxamide derivatives were equipotent to those bearing 1-azabicyclo[2.2.2]oct-3-yl moiety. The 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety was confirmed to adopt a boat-chair conformation on the basis of both NMR studies and X-ray analysis. In this series, endo-6-chloro-3, 4-dihydro-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2, 2, 4-trimethyl-2H-1, 4-benzoxazine-8-carboxamide showed the highest affinity for 5-HT3 receptors (Ki=0.019 nM), and a long-lasting 5-HT3 receptor antagonistic activity as evidenced by antagonism to the von Bezold-Jarisch reflex in rats. Such a long-lasting 5-HT3 receptor antagonism would be attributed to the introduction of both two methyl groups at the 2 position of the benzoxazine ring and the 9-methyl-9-azabicyclo[3.3.1]non-3-yl moiety, which adopts the boat-chair conformation.