RT Journal Article
SR Electronic
T1 Pharmacological Characterization of the Uroselective<em>Alpha</em>-1 Antagonist Rec 15/2739 (SB 216469): Role of the<em>Alpha</em>-1L Adrenoceptor in Tissue Selectivity, Part I
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1272
OP 1283
VO 281
IS 3
A1 A. Leonardi
A1 J. P. Hieble
A1 L. Guarneri
A1 D. P. Naselsky
A1 E. Poggesi
A1 G. Sironi
A1 A. C. Sulpizio
A1 R. Testa
YR 1997
UL http://jpet.aspetjournals.org/content/281/3/1272.abstract
AB Alpha adrenoceptor antagonists have been convincingly shown to be beneficial in reducing both subjective and objective indices of urethral obstruction in benign prostatic hyperplasia. Rec 15/2739 (SB 216469) is a novel alpha-1 adrenoceptor (alpha-1 AR) antagonist currently being developed for benign prostatic hyperplasia. When evaluated in radioligand binding assays with expressed animal or human alpha-1 ARs, Rec 15/2739 shows marked to moderate selectivity for thealpha-1a AR subtype. Its affinity for the recombinantalpha-2 AR subtypes or native dopaminergic D2 receptor was about 100-fold lower than that foralpha-1a AR subtype. In canine tissues, Rec 15/2739 was 20-fold more potent as an inhibitor of [3H]prazosin binding to prostate vis-a-vis aorta. Functional studies in isolated rabbit tissues also confirmed the uroselectivity of Rec 15/2739, with substantially higher affinity (K b = 2–3 nM) being observed in urethra and prostate, compared with ear artery and aorta (K b = 20–100 nM). The in vitro selectivity observed with Rec 15/2739 was confirmedin vivo in the anesthetized dog, comparing potency against norepinephrine- or hypogastric nerve stimulation-induced urethral contraction with its ability to reduce diastolic blood pressure. In this model, Rec 15/2739 had greater selectivity than any other alpha-1 AR antagonist examined, including terazosin and tamsulosin. Based on the low potency of prazosin and some of its structural analogs in the rabbit and dog lower urinary tract tissues, it appears that norepinephrine contracts these tissuesvia activation of the alpha-1L AR. Hence this alpha-1 AR subtype, rather than thealpha-1A AR, may mediate the contraction in vivo. The American Society for Pharmacology and Experimental Therapeutics