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Pharmacological characterization of A‐131701, a novel α 1 ‐adrenoceptor antagonist selective for α 1A ‐ and α 1D ‐compared to α 1B ‐adrenoceptors
Author(s) -
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.,
ChessWilliams Russell,
Noble Amanda J.,
Williams Michael,
Kerwin James F.
Publication year - 1998
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/(sici)1098-2299(199808)44:4<140::aid-ddr2>3.0.co;2-r
Subject(s) - antagonist , pharmacology , adrenergic receptor , chemistry , medicine , receptor
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]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 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 (pA 2 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 α 1 ‐adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α 2 ‐adrenoceptors. In isoflurane‐anesthetized dogs, A‐131701 antagonized epinephrine‐induced increases in intraurethral pressure (IUP) with a pseudo‐pA 2 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 the curve (AUC 0 → 60 min) 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‐pA 2 = 8.0) compared to concurrently measured MABP (pseudo‐pA 2 = 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 (pED 10 =. 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. Drug Dev. Res. 44:140–162, 1998. © 1998 Wiley‐Liss, Inc.