title: Characterization of some novel alpha 1-adrenoceptor antagonists in human hyperplastic prostate.
abstract: 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.
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Sect. 1, Taipei, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chueh
authors.forename: Ji-Wang
authors.initials: JW
authors.lastname: Chern
authors.forename: Chee-Min
authors.initials: CM
authors.lastname: Choong
authors.forename: Jih-Hwa
authors.initials: JH
authors.lastname: Guh
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D013154:Spleen / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: C470258:2-(4-(4-(2-methoxyphenyl)piperazinyl)butyl)amino-4-cyclohexylaminoquinazoline; C470257:4-(3-(4-(2-methoxyphenyl)piperazinyl)propyl)aminoquinazolin-2-carboxamide; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D010880:Piperidines; D011799:Quinazolines; D018340:Receptors, Adrenergic, alpha-1; C470256:ethyl 4-(3-(4-(2-methoxyphenyl)piperazinyl)propyl)aminoquinazolin-2-carboxylate