The pharmacological activity of 3-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)-2,3-dihydroimidaz o(1,2 -c)quinazolin-5(6H)-one (DC-015), a newly synthesized quinazoline derivative, was determined in rat isolated thoracic aorta and pressor responses were determined in spontaneously hypertensive rats (SHR). Experimental results indicated that DC-015 is an alpha 1-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 concentration (1.0 microM), 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 microM) in rat thoracic aorta was diminished by DC-015 (3 and 10 nM) and prazosin (10nM); 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 mm 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 alpha 1-adrenoceptor antagonist in vascular smooth muscle.

The hypotensive effect of DC-015, a newly synthesized quinazoline derivative, was investigated and compared with prazosin in spontaneously hypertensive rats (SHR). Intravenous administration of DC-015 and prazosin (both at 0.01, 0.05 and 0.1 mg/kg) induced a dose-dependent reduction of mean arterial pressure (MAP) which reached a maximal effect at 5 min after injection and persisted over 2 h in SHR. Furthermore, at higher doses DC-015 (0.1 mg/kg i.v. and 2.0 mg/kg orally, respectively) did not cause any significant changes in heart rate (HR); whereas the same doses of prazosin (0.1 mg/kg i.v. and 2.0 mg/kg orally, respectively) produced a decrease in HR which seems to parallel the time course of the hypotensive response in SHR. DC-015 and prazosin attenuated pressor responses to phenylephrine (10 &mgr;g/kg) but failed to inhibit the pressor effects of angiotensin II (0.5 &mgr;g/kg) even at the maximal hypotensive dose (0.1 mg/kg). This observation indicates that DC-015 appears to exert its hypotensive effect through alpha(1)-adrenoceptor blockade. On the other hand, in SHR fed a high-fat-high-cholesterol (HF-HC) diet, oral administration of DC-015 and prazosin (both at 1.0 mg/kg, twice a day) for 4 weeks caused significant reductions in total plasma cholesterol (CE), low-density lipoprotein (LDL)-cholesterol and total plasma triglyceride (TG). DC-015 therapy also increased high-density lipoprotein (HLD)-cholesterol levels, thus the ratio of total plasma cholesterol to HDL-CE was improved. In contrast, prazosin did not significantly increase the HDL-CE level in this study. It is concluded that DC-015 decreased MAP, plasma CE, LDL-CE, plasma TG and increased HDL-CE levels. DC-015 may have therapeutic potential as a potent antihypertensive drug via the alpha(1)-adrenoceptor antagonist. Concurrently, DC-015 may thus hold some advantage for the reduction of two of the major risk factors, hypertension and hyperlipidemia, for cardiovascular diseases. Copyright 1996 S. Karger AG, Basel

1. The effects of DC-015, a newly synthesized quinazoline derivative, on plasma lipids, lipoprotein levels and vascular reactivity were investigated in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). 2. The hypotensive effect of DC-015 was compared with prazosin in SHR. Intravenous administration of DC-015 and prazosin (both at 0.01, 0.05 and 0.1 mg/kg) induced dose-dependent reductions in mean arterial pressure (MAP) which reached a maximal effect 5 min after injection and persisted over 2 h in SHR. DC-015 decreased MAP with equal efficiency compared with prazosin. 3. The plasma levels of total cholesterol (CE), low-density lipoprotein (LDL)-CE and total triglyceride (TG) were markedly increased and the levels of high-density lipoprotein (HDL)-CE were markedly decreased in both high fat-high cholesterol (HF-HC) diet fed WKY and SHR. 4. In HF-HC diet fed WKY and SHR, the total plasma CE, LDL-CE and total plasma TG were significantly reduced after oral administration of DC-015 (1 mg/kg, twice a day) for 4 weeks. Furthermore, DC-015 therapy was associated with increased HDL-CE levels and thus the ratio of total CE to HDL-CE was improved. The antihyperlipidaemic effect of prazosin was less than that of DC-015. 5. Significantly attenuated median effective concentration (EC50) values and augmented maximal responses for phenylephrine-induced contraction of aortic rings were observed in HF-HC diet fed WKY and SHR. Endothelium-dependent relaxation to acetylcholine was impaired while endothelium-independent relaxation to nitroglycerin was well preserved. 6. Oral administration of DC-015 (1 mg/kg, twice a day) for 4 weeks significantly augmented EC50 values and attenuated maximal responses for phenylephrine-induced contraction of aortic rings in HF-HC diet fed WKY and SHR. Prazosin (1 mg/kg, twice a day) showed a lesser extent of efficiency than DC-015 at normalization of vasorelaxation in HF-HC diet fed WKY and SHR. 7. It is concluded that DC-015, a potent antihypertensive agent, may have additional advantage in also reducing hyperlipidaemia.

The hypotensive effect of DC-015, a newly synthesized quinazoline derivative, was investigated and compared with prazosin in spontaneously hypertensive rats (SHR). Intravenous administration of DC-015 and prazosin (both at 0.01, 0.05 and 0.1 mg/kg) induced a dose-dependent reduction of mean arterial pressure (MAP) which reached a maximal effect at 5 min after injection and persisted over 2 h in SHR. Furthermore, at higher doses DC-015 (0.1 mg/kg i.v. and 2.0 mg/kg orally, respectively) did not cause any significant changes in heart rate (HR); whereas the same doses of prazosin (0.1 mg/kg i.v. and 2.0 mg/ kg orally, respectively) produced a decrease in HR which seems to parallel the time course of the hypotensive response in SHR. DC-015 and prazosin attenuated pressor responses to phenylephrine (10 μg/kg) but failed to inhibit the pressor effects of angiotensin II (0.5 μg/kg) even at the maximal hypotensive dose (0.1 mg/kg). This observation indicates that DC-015 appears to exert its hypotensive effect through α(1)-adrenoceptor blockade. On the other hand, in SHR fed a high-fat-high-cholesterol (HF-HC) diet, oral administration of DC-015 and prazosin (both at 1.0 mg/kg, twice a day) for 4 weeks caused significant reductions in total plasma cholesterol (CE), low-density lipoprotein (LDL)-cholesterol and total plasma triglyceride (TG). DC-015 therapy also increased high-density lipoprotein (HLD)-cholesterol levels, thus the ratio of total plasma cholesterol to HDL-CE was improved. In contrast, prazosin did not significantly increase the HDL-CE level in this study. It is concluded that DC-015 decreased MAP, plasma CE, LDL-CE, plasma TG and increased HDL-CE levels. DC-015 may have therapeutic potential as a potent antihypertensive drug via the α(1)-adrenoceptor antagonist. Concurrently, DC-015 may thus hold some advantage for the reduction of two of the major risk factors, hypertension and hyperlipidemia, for cardiovascular diseases.