Pharmacological activity of DC-015, a novel potent and selective α1-adrenoceptor antagonist

The pharmacological activity of 3-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)-2,3-dihydroimidazo(1,2 -c)quinazolin-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 results indicated that DC-015 is an α₁-adrenoceptor-blocking agent in rat thoracic aorta as revealed by its competitive antagonism of phenylephrine-induced vasocontraction (pA₂ = 10.54 ± 0.55). These effects still persisted in denuded aorta. It was as potent as prazosin pA₂ = 10.04 ± 0.63). At higher concentrations (10 μM), DC-015 also expressed 5-hydroxytryptamine (5-HT) receptor competitive antagonism, but this 5-HT blocking effect was not found in the prazosin-administration group. [³H]Inositol monophosphate formation stimulated by phenylephrine (30 μM) in rat thoracic aorta was diminished by DC-015 (3 and 10 nM) and prazosin (10 nM); whereas the cAMP content of rat thoracic aorta was not altered by DC-015 and prazosin. Furthermore, intravenous 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 pressure which reached a maximal effect at 5 min after injection and persisted 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 dose of prazosin (0.1 mg kg^-1, i.v.) produced a decrease which seems to parallel the time course of the hypotensive response. We can conclude that the DC-015 is a potent, highly selective α₁-adrenoceptor antagonist in vascular smooth muscle.