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(1H,3H)-dione) is a novel compound previously shown to be selective for alpha-1a sites compared with alpha-1b adrenoceptors in radioligand binding studies and isolated tissue bioassays and to block canine urethral pressure (IUP) responses to exogenous alpha-1 adrenergic agonists to a greater extent than blood pressure responses. In conscious dogs in which IUP and mean arterial blood pressure (MABP) responses were measured periodically up to 24 hr, A-131701 blocked phenylephrine (PHE)-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 responses, 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 half-life of 0.4 to 0.8 hr and a bioavailability of 30 to 50% in dogs. Somewhat longer half-lives were observed in rat and monkey, with bioavailability values in the 25 to 30% range. Evidence of nonlinearity of pharmacokinetics was obtained in dogs and monkeys. Pharmacodynamic analysis revealed differences between A-131701 and nonselective alpha-1 adrenoceptor antagonists in selectivity for prostatic versus vascular alpha-1 adrenoceptors based on either extent or duration of blockade, which were either similar to or superior to compounds such as tamsulosin or REC 15/2739. These data demonstrate that A-131701 selectively blocks canine prostatic alpha-1 adrenoceptors for prolonged periods compared with MABP responses in vivo. Therefore, A-131701 should have clinical utility in the pharmacotherapy of benign prostatic hyperplasia.
Hancock
A A
AA
Abbott Laboratories, Pharmaceutical Products Division, Abbott Park, Illinois, USA.
Brune
M E
ME
Witte
D G
DG
Marsh
K C
KC
Katwala
S
S
Milicic
I
I
Ireland
L M
LM
Crowell
D
D
Meyer
M D
MD
Kerwin
J F
JF
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D005260:Female; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D054833:Isoindoles; D008252:Macaca fascicularis; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects*; D011744:Pyrimidinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014521:Urethra
C108685:A 131701; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D054833:Isoindoles; D011744:Pyrimidinones; D010656:Phenylephrine