SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2,3-DIHYDROBENZOFURAN-7-CARBOXAMIDE DERIVATIVES AS POTENT SEROTONIN-3 (5-HT3) RECEPTOR ANTAGONISTS

A series of abicyclo-3-yl)-2,3-dihydrobenzofuran-7-carboxamide derivat ives were synthesized and evaluated for serotonin-3 (5-HT3) receptor a ntagonistic activities assessed by 5-HT3 receptor binding (in vitro) a nd by the ability to antagonize the von Bezold-Jarisch reflex in rats (in vivo). In these compounds, 1-azabicyclo[2.2.2]oct-yl derivatives w ere 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 phar macological activities (dimethyl > monomethyl > dihydro). Furthermore, the stereoisomers of dimethyl-, monomethyl-, and dihydrobenzofuran de rivatives were prepared to evaluate the stereoselectivity of their 5-H T3 receptor binding affinities. Concerning the basic part, the compoun ds bearing (S)-1-azabicyclo[2.2.2[octan-3-yl moiety were more potent t han their counterparts. With respect to the methyl substituent at posi tion 2 of the dihydrobenzofuran ring, the rank order of the potency wa s dimethyl greater than or equal to (2S)-methyl > (2R)-methyl > dihydr o. These results suggest that the (2S)-methyl group of the dihydrobenz ofuran part contributes to the enhancement of the pharmacological acti vity. Among these compounds, o-2,3-dihydro-2,2-dimethylbenzofuran-7-ca rboxamide hydrochloride (24) showed the highest affinity for 5-HT3 rec eptors (K-i=0.055 nM), and the most potent antagonistic activity on th e von Bezold-Jarisch reflex (ED(50) =0.18 mu g/kg i.v.).