Characterization of some novel alpha 1-adrenoceptor antagonists in human hyperplastic prostate.

We synthesized some quinazoline-based compounds, such as FH-71 (ethyl 4-(3-(4-(2-methoxyphenyl)piperazinyl)aminoquinazolin-2-carboxylate), 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,9 alpha-epoxymethano-15S-hydroxy-prosta-5Z,13E-dienoic acid)-induced contractions in rat aorta, suggesting alpha(1)-adrenoceptor antagonist properties. With rat vasa deferentia and spleens as the functional alpha(1A)- 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 microM) 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.