Pharmacological characterization of A-131701, a novel α₁-adrenoceptor antagonist selective for α(1A)- and α(1D)-compared to α(1B)-adrenoceptors

New compounds selective for α(1A)-adrenoceptors in the prostate may offer enhanced efficacy for benign prostatic hyperplasia (BPH), with fewer side effects than current treatment. A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy- 2,3,3a,4,5,9b,hexahydro-[1H]-benz[e]isoindol-2- yl)ethyl]pyridol]3',4':4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione), from a novel class of benz[e]isolindole pyridothienopyrimidines and pyridothienopyrazines, is selective for α(1a)- and α(1d)-adrenoceptors in radioligand binding studies (0.22 nM at α(1a)-, 0.97 nM at α(1d))- compared to α(1b)-sites (2.5 nM) and in isolated tissue bioassays (pA₂ values of 8.9-9.0 for α(1A)-receptors in rat vas deferens or canine prostate strips, 9.1 at α(1D)-sites (rat aorta)), compared to 7.9 at α(1B)-sites (rat spleen). A-131701 also potently blocked radioligand binding to α₁- adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α₂-adrenoceptors. In isoflurane-anesthetized dogs, A-131701 antagonized epinephrine-induced increases in intraurethral pressure (IUP) with a pseudo-pA₂ value of 8.17. In spontaneously hypertensive rats. A- 131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under curve (AUC₀ →₆₀ min for the hypotensive response was dose-related, with long index value A-131701 of 5.33, suggesting a selectivity of >600-fold comparing IUP to MABP effects. In pentobarbital-anesthetized dogs, A-131701 was more potent in blocking phenylephrine (PHE)-induced increases in IUP (pseudo-pA₂ = 8.0), compared to concurrently measured MABP (pseudo-pA₂ = 7.2), or sixfold selective. Doses greater than 1,000 nmol/kg i.v. of A-131701 were required to lower blood pressure by 10 mm Hg in these dogs (pED₁₀ = 5.57), indicating a uroselectivity ratio of >250, superior to doxazosin, terazosin, or tamsulosin. Thus, A-131701 is selective for α(1A)- and α(1D)- vs. α(1B)- adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH.