Antihypertensive effects of AT-112, a newly synthesized quinazoline derivative, in spontaneously hypertensive rats.

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.