Design, synthesis and alpha1-adrenoreceptor blocking activity of new arylpiperazines containing acetophenone substituents.

Alpha1-AR antagonists are currently first-line therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we report the synthesis of a new series of arylpiperazine derivatives containing acetophenone (3-17) which possess alpha1-adrenoreceptor blocking activity. The in vitro alpha1-adrenoreceptor blocking activity of each derivative was first screened using rabbit thoracic aortic rings by measuring the relaxation response (%) activated by (-)-noradrenaline (3 microM). Compounds 6 and 7 with 2,5-dimethoxy and 2-ethoxy substituent were found to have significant vasodilatory effect. Since the presence of a chiral carbon in the structure, 6 and 7 together with their enantiomers 14-17 were further evaluated by testing diastolic effect on rabbit thoracic aorta, prostate and bladder smooth muscle. The S-enantiomer was found to have more potent diastolic activity than the R-enantiomer and racemate, 17 being the most effective alpha1-adrenoreceptor antagonist. In order to assess tissue selectivity, the antagonistic effect of 17 on the (-)-noradrenaline induced contractile response of isolated rat vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)) was characterized finally. Compared with naftopidil (1) and terazosin, compound 17 exhibited higher selectivity (18-fold) for the alpha(1D)-adrenoceptor subtype as compared to the alpha(1B)-adrenoceptor subtype, indicating less cardiovascular side effects for the treatment of LUTS/BPH. These data suggest that the acetophenone is a new effective adrenergic receptor ligand as well as incentivizes further research regarding pharmacological properties of chiral molecules.