title: Antihypertensive effects of AT-112, a newly synthesized quinazoline derivative, in spontaneously hypertensive rats.
abstract: The purpose of this study was to investigate the anti-hypertensive effect and possible mechanism of action of 2-(4-phenyl-1-piperazinyl)methyl-2,3-dihydroimidazo[1,2- c]quinazolin-5(6H)-one (AT-112), a newly synthesized ketanserin derivative, on in vivo and in vitro models. In vivo, central and peripheral administration of AT-112 produced a dose-dependent decrease of arterial blood pressure in conscious spontaneously hypertensive rats (SHR). In in vitro study, the vasodilating effect of AT-112 on isolated thoracic aorta was endothelium-independent. AT-112 was found to be a potent alpha 1-adrenoceptor blocking agent in the rat thoracic aorta as revealed by its competitive antagonism of phenylephrine (pA2 = 9.82 +/- 0.19), but was found to have noncompetitive antagonism to 5-HT. The IC50 of ketanserin and AT-112 to phenylephrine were 27.8 nM and 0.36 nM, respectively, and to 5-HT were 5.73 nM and 0.44 microM, respectively. Competition binding studies demonstrated that the affinity of AT-112 to alpha 1-adrenoceptor (Ki = 2.01 +/- 0.09 nM) was significantly higher than that of alpha 2-adrenoceptor (Ki = 3.86 +/- 0.64 MM). Based on the results of these in vivo, in vitro and competition binding studies, AT-112 is a potent antihypertensive agent, and its antihypertensive action is mainly mediated by the blockade of the alpha 1-adrenoceptor.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D010656:Phenylephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D012701:Serotonin / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: C096497:AT 112; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D011799:Quinazolines; D010656:Phenylephrine; D012701:Serotonin; D003000:Clonidine; D011224:Prazosin