Pharmacological characterization of A‐131701, a novel α1‐adrenoceptor antagonist selective for α1A‐ and α1D‐compared to α1B‐adrenoceptors

Autor: Hancock, Arthur A., Buckner, Steven A., Brune, Michael E., Katwala, Sweta, Milicic, Ivan, Ireland, Lynne M., Morse, Patricia A., Knepper, Sheila M., Meyer, Michael D., Chapple, Christopher R., Chess‐Williams, Russell, Noble, Amanda J., Williams, Michael, Kerwin, James F.
Zdroj: Drug Development Research; August 1998, Vol. 44 Issue: 4 p140-162, 23p
Abstrakt: New compounds selective for α1A‐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]pyrido[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 α1a‐ and α1d‐adrenoceptors in radioligand binding studies (0.22 nM at α1a‐, 0.97 nM at α1d‐) compared to α1b‐sites (2.5 nM) and in isolated tissue bioassays (pA2values of 8.9–9.0 for α1A‐receptors in rat vas deferens or canine prostate strips, 9.1 at α1D‐sites (rat aorta)), compared to 7.9 at α1B‐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‐pA2value of 8.17. In spontaneously hypertensive rats, A‐131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under the curve (AUC0→60min) for the hypotensive response was dose‐related, with a log index value for 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 α1A‐ and α1D‐ vs. α1B‐adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH. Drug Dev. Res. 44:140–162, 1998. © 1998 Wiley‐Liss, Inc.
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