title: Synthesis and structure-activity relationships of 2,3-dihydrobenzofuran-7-carboxamide derivatives as potent serotonin-3 (5-HT3) receptor antagonists.
abstract: 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 (dimethyl > monomethyl > dihydro). 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 dimethyl > or = (2S)-methyl > (2R)-methyl > dihydro. 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.).
authors.affiliation: Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kuroita
authors.forename: M
authors.initials: M
authors.lastname: Yasumoto
authors.forename: K
authors.initials: K
authors.lastname: Inaba
authors.forename: M
authors.initials: M
authors.lastname: Sakamori
authors.forename: S
authors.initials: S
authors.lastname: Takehara
authors.forename: T
authors.initials: T
authors.lastname: Kawakita
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D012702:Serotonin Antagonists; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D012702:Serotonin Antagonists