title: Design, synthesis and alpha1-adrenoreceptor blocking activity of new arylpiperazines containing acetophenone substituents.
abstract: 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.
authors.forename: J J
authors.initials: JJ
authors.lastname: Huang
authors.forename: Y J
authors.initials: YJ
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Zhu
authors.forename: M
authors.initials: M
authors.lastname: Yuan
authors.forename: L
authors.initials: L
authors.lastname: Huang
mesh_terms: D000098:Acetophenones / Q000138:chemical synthesis* / Q000494:pharmacology*; D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D015195:Drug Design; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D013154:Spleen / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D058668:Adrenergic alpha-1 Receptor Antagonists; D007202:Indicators and Reagents; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D014665:Vasodilator Agents