PHARMACOLOGICAL ACTIVITY OF DC-015, A NOVEL POTENT AND SELECTIVE ALPHA(1)-ADRENOCEPTOR ANTAGONIST

The pharmacological activity of hyl)-2,3-dihydroimidazo(1,2-c)quinazol in-5(6H)-one (DC-015), a newly synthesized quinazoline derivative, was determined in rat isolated thoracic aorta and presser responses were determined in spontaneously hypertensive rats (SHR). Experimental resu lts indicated that DC-015 is an alpha(1)-adrenoceptor-blocking agent i n rat thoracic aorta as revealed by its competitive antagonism of phen ylephrine-induced vasocontraction (pA(2) = 10.54 +/- 0.55). These effe cts still persisted in denuded aorta. It was as potent as prazosin (pA (2) = 10.04 +/- 0.63). At higher concentrations (1.0 mu M), DC -015 al so expressed 5-hydroxytryptamine (5-HT) receptor competitive antagonis m, but this 5-HT blocking effect was not found in the prazosin-adminis tration group. [H-3]Inositol monophosphate formation stimulated by phe nylephrine (30 mu M) in rat thoracic aorta was diminished by DC-015 (3 and 10 nM) and prazosin (10 nM); whereas the cAMP content of rat thor acic aorta was not altered by DC-015 and prazosin. Furthermore, intrav enous administration of DC-015 and prazosin (both at 0.01, 0.05 and 0. 1 mg kg(-1)) induced a dose-dependent reduction of mean arterial press ure which reached a maximal effect at 5 min after injection and persis ted over 2 h in SHR. A higher dose of DC-015 (0.1 mg kg(-1), i.v.) did not cause any significant changes in heart rate, whereas, the same do se of prazosin (0.1 mg kg(-1), i.v.) produced a decrease which seems t o parallel the time course of the hypotensive response. We can conclud e that the DC-015 is a potent, highly selective alpha(1)-adrenoceptor antagonist in vascular smooth muscle.