Synthesis and Serotonin 2 (5-HT_2) Receptor Antagonist Activity of 5-Aminoalkyl-Substituted Pyrrolo[3,2-c]azepines and Related Compounds
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概要
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A series of 5-aminoalkylpyrrolo[3,2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT_2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT_2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring.Compound 18a, 5-[3-]4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl-1,4,5,6,7,8,-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT_2 receptor antagonist activity with weak α_1 adrenoceptor blocking activity and no significant D_2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT_2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT_2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT_2 receptor antagonist activity (pA_2=8.98±0.06) and high selectivity versus other receptors.SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC_<50>=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolitic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher.
- 公益社団法人日本薬学会の論文
- 2000-05-01
著者
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Inomata Norio
Suntory Institute for Biomedical Research
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Mizuno A
Suntory Institute For Biomedical Research
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Inomata N
Suntory Institute For Biomedical Research
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Inomata Norio
Laboratory Of Experimental:molecular Pharmacology Suntory Institute For Biomedical Research
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Shibata M
Fumakilla Ltd.
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Mizuno Akira
Suntory Institute For Biomedical Research
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Shimamoto T
Suntory Institute For Biomedical Research
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OGATA Atsto
Suntory Institute for Biomedical Research
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KAMEI Tomoe
Suntory Institute for Biomedical Research
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SHIBATA Makoto
Suntory Institute for Biomedical Research
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SHIMAMOTO Tetsuo
Suntory Institute for Biomedical Research
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HAYASHI Yasuhiro
Suntory Institute for Biomedical Research
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NAKANISHI Kyoko
Suntory Institute for Biomedical Research
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TAKIGUCHI Chikako
Suntory Institute for Biomedical Research
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OKA Naomi
Suntory Institute for Biomedical Research
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Mizuno A
Meiji Pharmaceutical Univ. Tokyo Jpn
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Ogata A
Suntory Institute For Biomedical Research
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Kamei T
Suntory Institute For Biomedical Research
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Nakanishi K
Suntory Institute For Biomedical Research
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Hayashi Yasuhiro
Suntory Biomedical Research Limited
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Ogata Atsuto
Suntory Institute for Biomedical Research
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