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.
Honda
K
K
Takenaka
T
T
Miyata-Osawa
A
A
Terai
M
M
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011941:Receptors, Adrenergic / Q000187:drug effects*; D013237:Stereoisomerism; D000096926:Benzenesulfonamides
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D003000:Clonidine; D004983:Ethanolamines; D010627:Phenethylamines; D011224:Prazosin; D011941:Receptors, Adrenergic; C048230:YM 11133; C032473:amosulalol; D000096926:Benzenesulfonamides