Synthesis and Structure-Activity Relationships of 2,3-Dihydrobenzofuran-7-carboxamide Derivatives as Potent Serotonin-3 (5-HT3) Receptor Antagonists
| Autor: | K. Inaba, Masamitsu Sakamori, Mitsuyoshi Yasumoto, Takanobu Kuroita, Takeshi Kawakita, Shuzo Takehara |
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| Rok vydání: | 1994 |
| Předmět: |
Male
medicine.drug_class Stereochemistry Substituent Carboxamide In Vitro Techniques 5-HT3 receptor Structure-Activity Relationship chemistry.chemical_compound 5-HT3 Receptor Antagonist Reflex Drug Discovery medicine Animals Structure–activity relationship Rats Wistar Benzofurans Bicyclic molecule biology Hemodynamics Biological activity General Chemistry General Medicine Rats chemistry biology.protein Stereoselectivity Serotonin Antagonists |
| Zdroj: | Chemical and Pharmaceutical Bulletin. 42:95-100 |
| ISSN: | 1347-5223 0009-2363 |
| DOI: | 10.1248/cpb.42.95 |
| Popis: | A series of N-(azabicyclo-3-yl)-2,3-dihydrobenzofuran-7-carboxamide derivatives were synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activities assessed by 5-HT3 receptor binding (in vitro) and by the ability to antagonize the von Bezold-Jarisch reflex in rats (in vivo). In these compounds, 1-azabicyclo[2.2.2]oct-3-yl derivatives were more potent than 8-methyl-8-azabicyclo[3.2.1]oct-3-yl derivatives for 5-HT3 receptor antagonistic activities. The introduction of methyl groups at position 2 of the dihydrobenzofuran ring increased the pharmacological activities (dimethylmonomethyldihydro). Furthermore, the stereoisomers of dimethyl-, monomethyl-, and dihydrobenzofuran derivatives were prepared to evaluate the stereoselectivity of their 5-HT3 receptor binding affinities. Concerning the basic part, the compounds bearing (S)-1-azabicyclo[2.2.2]octan-3-yl moiety were more potent than their counterparts. With respect to the methyl substituent at position 2 of the dihydrobenzofuran ring, the rank order of the potency was dimethylor = (2S)-methyl(2R)-methyldihydro. These results suggest that the (2S)-methyl group of the dihydrobenzofuran part contributes to the enhancement of the pharmacological activity. Among these compounds, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2,3-dihydro-2,2- dimethylbenzofuran-7-carboxamide hydrochloride (24) showed the highest affinity for 5-HT3 receptors (Ki = 0.055 nM), and the most potent antagonistic activity on the von Bezold-Jarisch reflex (ED50 = 0.18 microgram/kg i.v.). |
| Databáze: | OpenAIRE |
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