Pharmacological Activity of DC−015, a Novel Potent and Selective α1-Adrenoceptor Antagonist

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Abstract
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 pressor 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 = 10ṁ54 ± 0ṁ55). These effects still persisted in denuded aorta. It was as potent as prazosin (pA2 = 10ṁ04 ± 0ṁ63). At higher concentrations (1ṁ0 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 0ṁ01, 0ṁ05 and 0ṁ1 mg kg11) 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 (0ṁ1 mg kg−1, i.v.) did not cause any significant changes in heart rate, whereas, the same dose of prazosin (0ṁ1 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.
Funding Information
  • National Science Council of the Republic of China (NSC-83-0412-B-016-021 MO4)

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