Pharmacological activity of DC-015, a novel potent and selective alpha 1-adrenoceptor antagonist.
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.
Yen
M H
MH
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Sheu
J R
JR
Peng
I H
IH
Lee
Y M
YM
Chern
J W
JW
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006973:Hypertension / Q000188:drug therapy*; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011224:Prazosin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D010716:Phosphatidylinositols; D011799:Quinazolines; D012702:Serotonin Antagonists; C100699:DC 015; D010656:Phenylephrine; D000242:Cyclic AMP; D011224:Prazosin