ACTIONS OF A-131701, A NOVEL, SELECTIVE ANTAGONIST FOR ALPHA-1A COMPARED WITH ALPHA-1B ADRENOCEPTORS ON INTRAURETHRAL AND BLOOD-PRESSURE RESPONSES IN CONSCIOUS DOGS AND A PHARMACODYNAMIC ASSESSMENT OF IN-VIVO PROSTATIC SELECTIVITY

A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]- benz[e]isoindol-2-yl)ethyl]pyrido [3',4': 4,5]thieno[3,2-d]pyrimidine- 2,4(1 H,3H)-dione) is a novel compound previously shown to be selectiv e for alpha-1 a sites compared with alpha-1b adrenoceptors in radiolig and binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agon ists to a greater extent than blood pressure responses. In conscious d ogs in which IUP and mean arterial blood pressure (MABP) responses wer e measured periodically up to 24 hr, A-131701 blocked phenylephrine (P HE)-induced increases in IUP to a greater extent than MABP responses, and the blockade of the IUP effects of PHE was significantly different from control for up to 12 hr after doses greater than 0.3 mg/kg p.o., whereas blood pressure effects were of a lesser extent and duration. In addition to the weak antagonism of PHE-induced blood pressure respo nses, A-131701 also exhibited minimal effects on basal blood pressure in the dog, unlike terazosin, doxazosin or tamsulosin. Pharmacokinetic analysis of plasma samples from dogs indicated that A-131701 had a ha lf-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. S omewhat longer half-lives were observed in rat and monkey, with bioava ilability values in the 25 to 30% range. Evidence of nonlinearity of p harmacokinetics was obtained in dogs and monkeys. Pharmacodynamic anal ysis revealed differences between A-131701 and nonselective alpha-1 ad renoceptor antagonists in selectivity for prostatic versus vascular al pha-1 adrenoceptors based on either extent or duration of blockade, wh ich were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively bloc ks canine prostatic alpha-1 adrenoceptors for prolonged periods compar ed with MABP responses in vivo. Therefore, A-131701 should have clinic al utility in the pharmacotherapy of benign prostatic hyperplasia.