|Title:||Characterization of Some Novel Alpha(1)-Adrenoceptor Antagonists in Human Hyperplastic Prostate||Authors:||CHUEH, SHIH-CHIEH
|Keywords:||alpha(1)-adrenoceptor antagonist;alpha(1)-adrenoceptor subtype;hyperplastic prostate;human;ALPHA-ADRENOCEPTORS;SMOOTH-MUSCLE||Issue Date:||2002||Journal Volume:||v.445||Journal Issue:||n.1-2||Start page/Pages:||125-131||Source:||EUROPEAN JOURNAL OF PHARMACOLOGY||Abstract:||
We synthesized some quinazoline-based compounds, such as FH- 71 (ethyl 4- (3-(4-(2-methoxyphenyl)piperazinyl) aminoquinazolin-2carboxylate), EW-65 ( 4-(3-(4-(2- methoxyphenyl)piperazinyl)propyl)aminoquinazolin-2- carboxamide) and EW-154 (2-(4-(4-(2-methoxyphenyl) piperazinyl)butyl)amino -4-cyclohexylamino-quinazolin), and then characterized their pharmacological properties in several tissues, All of these compounds produced potent inhibition of phenylephrine but not high K+ or U46619 (11 alpha,9alpha-epoxymethano-15S-hydroxy-prosta-5Z, 13E-dienoic acid)-induced contractions in rat aorta, suggesting alpha1- adrenoceptor antagonist properties. With rat vasa deferentia and spleens as the functional alpha(1 A)- and alpha(1B)- adrenoceptor models, respectively, FH-71 exhibited greater antagonistic potency in rat vas deferens, EW-154 in rat spleen, and EW-65 had similar effects in both tissues. The potency ratios of terazosin, FH-71, EW-65 and EW-154 against phenylephrine-induced contractions in rat vas deferens/ spleen were 1. 19.04, 0.39 and 0.09. respectively . The results suggest that FH-71 is a selective alpha(1A)- adrenoceptor antagonist, whereas EW-154 exhibits more antagonistic selectivity against alpha(1B)-adrenoceptors. FH -71 also showed a greater potency than EW-65 and EW-154 against phenylephrine-induced contraction in human hyperplastic prostate. The pA(2) values were 8.34, 7.44 and 7,05, respectively. Furthermore, FH-71 and EW-65 were not cytotoxic whereas EW- 154 (all in 10 muM) had a massive toxic effect (more than 80%) in human prostatic smooth muscle cells. These data show FH-71 to be a potent and selective alpha(1A)-adrenoceptor antagonist with activity in human hyperplastic prostate. (C) 2002 Elsevier Science B.V All rights reserved.
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