title: In vitro and in vivo uroselectivity of B8805-033, an antagonist with high affinity at prostatic alpha1A- vs. alpha1B- and alpha1D-adrenoceptors.
abstract: We have investigated the pharmacological properties of B8805-033 [(+/-)- 1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl] amino]-2,4(1H,3H)-pyrimidinedione], a new alpha1A-adrenoceptor (AR) selective antagonist. In radioligand binding studies, B8805-033 was 150- to 1200-fold selective for alpha1A-ARs (pKi rat cerebral cortex 8.70, cloned human receptor 7.71) relative to alpha1B-ARs (pKi rat cerebral cortex 5.60, rat liver 5.39, cloned human receptor 5.16) and alpha1D-ARs (pKi cloned human receptor 5.49). B8805-033 inhibited noradrenaline (NA) induced contractions mediated by alpha1A-ARs in rat vas deferens and rabbit and human prostate (pA2 7.62-8.40) much more potently than those mediated by alpha1B-ARs in guinea pig and mouse spleen or by alpha1D-ARs in rat aorta and pulmonary artery (pA2 5.21-5.52). With the exception of a high agonist affinity at 5-HT1A receptors (pKi 9.74 in pig cortex, pD2 6.82 for contraction of rabbit basilar artery) and a moderate to low affinity at histamine H1-receptors (pA2 6.74) and beta1-ARs (pA2 5.75), B8805-033 did not interact with a number of other neurotransmitter receptors (pKi or pA2<5.0). From the i.v. doses of B8805-033 to either inhibit the urethral pressure response to NA by 50% (29 nmol/kg) or to evoke a fall in diastolic blood pressure by 25% (1.54 micromol/kg) in anaesthetized dogs, an urethral/ vascular selectivity ratio of 52 was obtained, far exceeding that found for the nearly unselective prazosin (ratio 1.8). We conclude that B8805-033 is a highly alpha1A-AR selective antagonist, which may potentially be useful as pharmacological tool to investigate alpha1-AR heterogeneity and in the treatment of benign prostatic hyperplasia.
authors: Research Department, Byk Gulden, Konstanz, Germany. manfrid.eltze@byk.de
authors: M
authors: M
authors: Eltze
authors: R
authors: R
authors: Boer
authors: M C
authors: MC
authors: Michel
authors: P
authors: P
authors: Hein
authors: R
authors: R
authors: Testa
authors: W R
authors: WR
authors: Ulrich
authors: N
authors: N
authors: Kolassa
authors: K H
authors: KH
authors: Sanders
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004147:Dioxins / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D013045:Species Specificity; D013552:Swine
chemical_list: C438684:1,3,5-trimethyl-6-((3-(4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl)propyl)amino)-2,4(1H,3H)-pirymidinedione; D000317:Adrenergic alpha-Antagonists; D004147:Dioxins; D011744:Pyrimidinones; D011942:Receptors, Adrenergic, alpha