In Vitro And In Vivo Uroselectivity Of B8805-033, An Antagonist With High Affinity At Prostatic Alpha(1a)- Vs. Alpha(1b)- And Alpha(1d)-Adrenoceptors

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 alpha (1A)-adrenoceptor (AR) selective antagonist. In radioligand binding studies, B8805-033 was 150- to 1200-fold selective for alpha (1A)-ARs (pK(i) rat cerebral cortex 8.70, cloned human receptor 7.71) relative to alpha (1B)-ARs (pK(i) rat cerebral cortex 5.60, rat liver 5.39, cloned human receptor 5.16) and alpha (1D)-ARs (pK(i) cloned human receptor 5.49). B8805-033 inhibited noradrenaline (NA) induced contractions mediated by alpha (1A)-ARs in rat vas deferens and rabbit and human prostate (pA(2) 7.62-8.40) much more potently than those mediated by alpha (1B)-ARs in guinea pig and mouse spleen or by alpha (1D)-ARs in rat aorta and pulmonary artery (pA(2) 5.21-5.52). With the exception of a high agonist affinity at 5-HT1A receptors (pK(i) 9.74 in pig cortex, pD(2) 6.82 for contraction of rabbit basilar artery) and a moderate to low affinity at histamine H-1-receptors (pA(2) 6.74) and beta (1)-ARs (pA(2) 5.75), B8805-033 did not interact with a number of other neurotransmitter receptors (pK(i) or pA(2)<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 mol/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 alpha (1A)-AR selective antagonist, which may potentially be useful as pharmacological tool to investigate alpha (1)-AR heterogeneity and in the treatment of benign prostatic hyperplasia.