title: Studies on YM-12617: a selective and potent antagonist of postsynaptic alpha 1-adrenoceptors.
abstract: YM-12617, 5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2 -methoxybenzenesulfonamide HCl is a structurally new type of extremely potent alpha 1-adrenoceptor antagonist. Its alpha-adrenoceptor blocking properties have been compared with those of prazosin, phentolamine and yohimbine using both pharmacological and 3H-ligand binding techniques in vitro and in vivo. In the isolated rabbit aorta, a tissue known to contain mainly alpha 1-adrenoceptors at postjunctional sites, YM-12617 competitively antagonized noradrenaline-induced contraction with a pA2 value of 10.11. Although YM-12617 was also a competitive antagonist toward clonidine at prejunctional alpha 2-adrenoceptors in the isolated rat vas deferens, its affinity for these receptors (pA2 = 6.41) was 5,000 times lower than that displayed for the postjunctional alpha 1-adrenoceptors in the isolated rabbit aorta. YM-12617 displaced both 3H-WB 4101 and 3H-clonidine binding to rat brain membranes; however, the affinity of YM-12617 for alpha 1-adrenoceptors (pKi = 9.64) was 3800 times higher than that for alpha 2-adrenoceptors (pKi = 6.06). Based on pA2 values obtained in the isolated tissues and pKi values in the binding assays, YM-12617 was 2-18, 36-117 and 1,740-5,750 times more potent than prazosin, phentolamine and yohimbine in antagonizing alpha 1-adrenoceptors, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: T
authors.initials: T
authors.lastname: Takenaka
authors.forename: A
authors.initials: A
authors.lastname: Miyata-Osawa
authors.forename: M
authors.initials: M
authors.lastname: Terai
authors.forename: K
authors.initials: K
authors.lastname: Shiono
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014316:Tritium; D014649:Vas Deferens / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D000317:Adrenergic alpha-Antagonists; D000068438:Brimonidine Tartrate; D003000:Clonidine; D004146:Dioxanes; D010656:Phenylephrine; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D013449:Sulfonamides; D014316:Tritium; C044648:YM 12617; D000096926:Benzenesulfonamides; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane