title: Blockade and postjunctional vascular alpha 1- and alpha 2-adrenoceptors in pithed rat by the enantiomers of WB-4101.
abstract: The enantiomers of WB-4101 were evaluated for their ability to antagonize the alpha 1-adrenoceptor mediated pressor effect of cirazoline and the alpha 2-adrenoceptor mediated pressor effect of UK-14,304 in pithed rats. The (S)-stereoisomer of WB-4101 was more potent than the enantiomeric (R)-isomer in antagonizing both cirazoline and UK-14,304. The difference in potency between the enantiomers in blocking cirazoline was 37-fold in contrast to an enantiomeric difference of less than 3-fold for antagonizing UK-14,304. Based on DR2 values (i.e., dose of WB-4101 isomer in mg/kg required to produce a 2-fold rightward shift in the dose-response curves of cirazoline and UK-14,304) obtained in vivo from Schild regressions, alpha 1/alpha 2 selectivity ratios were calculated. While the (S)-enantiomer displays a 187-fold selectivity for alpha 1-adrenoceptors, the (R)-enantiomer is only approximately 13-fold selective for alpha 1-adrenoceptors. These results indicate that the alpha 1- and alpha 2-adrenoceptor blocking activity of WB-4101 resides predominantly in the (S)-enantiomer and that both enantiomers of WB-4101 are selective alpha 1-adrenoceptor antagonists in vivo. However the degree of alpha 1-adrenoceptor selectivity differs from each enantiomer, and the enantiomeric activity ratios differ for each alpha-adrenoceptor subtype.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000037:antagonists & inhibitors; D000818:Animals; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000502:physiology; D000068438:Brimonidine Tartrate; D004146:Dioxanes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000037:antagonists & inhibitors; D007536:Isomerism; D008297:Male; D011810:Quinoxalines / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D012044:Regression Analysis; D013116:Spinal Cord / Q000502:physiology
chemical_list: D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000959:Antihypertensive Agents; D004146:Dioxanes; D004147:Dioxins; D007093:Imidazoles; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D000068438:Brimonidine Tartrate; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C014282:cirazoline