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, B88 05-033 was 150- to 1200-fold selective for alpha (1A)-ARs (pK(i) rat cerebr al 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) an d alpha (1D)-ARs (pK(i) cloned human receptor 5.49). B8805-033 inhibited no radrenaline (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 potentl y than those mediated by alpha (1B)-ARs in guinea pig and mouse spleen or b y 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 mod erate 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 neurotr ansmitter 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 <mu>mol/kg) in anaesthetized dogs, an urethral/vascular selectivity ratio of 52 was obtain ed, far exceeding that found for the nearly unselective prazosin (ratio 1.8 ). We conclude that B8805-033 is a highly alpha (1A)-AR selective antagonis t, which may potentially be useful as pharmacological tool to investigate a lpha (1)-AR heterogeneity and in the treatment of benign prostatic hyperpla sia.