Adrenoceptor blocking properties of the stereoisomers of amosulalol (YM-09538) and the corresponding desoxy derivative (YM-11133).

The antagonist potencies of amosulalol (YM-09538), its stereoisomers and the corresponding desoxy derivative (YM-11133) have been compared at alpha-1, alpha-2, beta-1 and beta-2 adrenoceptors in isolated organs in vitro and in radioligand binding experiments. In isolated peripheral tissues, (+/-)-, (-)- and (+)-amosulalol and YM-11133 are selective alpha-1 adrenoceptor antagonists over alpha-2 adrenoceptors by two orders of magnitude and are nonselective beta adrenoceptor antagonists. (+)-Amosulalol and YM-11133 were 14 and 9.3 times more potent than (-)-amosulalol as alpha-1 adrenoceptor antagonists but approximately 50 and 40 times less potent antagonists at beta adrenoceptors than (-)-amosulalol, respectively. The adrenoceptor blocking profile of the racemate is approximately 2-fold less potent than that of the (+)-isomer at alpha and that of the (-)-isomer at beta adrenoceptors. The affinities of (+/)-, (-)- and (+)-amosulalol and YM-11133 obtained from radioligand binding experiments (pKi) using rat brain membrane correlated well with those obtained from in vitro experiments (pA2) at alpha-1 (r = 0.884), alpha-2 (r = 0.977), beta-1 (r = 0.993) and beta-2 (r = 0.971) adrenoceptors. These results indicate that the stereochemical requirements of alpha and beta adrenoceptors differ for the stereoisomers of amosulalol with the alpha adrenoceptor subtypes favoring the (+)-isomer and the desoxy form and the beta subtypes favoring the (-)-isomer.