Vol. 281, Issue 3, 1272-1283, 1997

Pharmacological Characterization of the Uroselective Alpha-1 Antagonist Rec 15/2739 (SB 216469): Role of the Alpha-1L Adrenoceptor in Tissue Selectivity, Part I

A. Leonardi, J. P. Hieble, L. Guarneri, D. P. Naselsky, E. Poggesi, G. Sironi, A. C. Sulpizio and R. Testa

Pharmaceutical R&D Division, Recordati S.p.A., 20148 Milano, Italy (A.L., L.G., E.P., G.S., R.T.) and Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania (J.P.H., D.P.N., A.C.S.)

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 the alpha-1a AR subtype. Its affinity for the recombinant alpha-2 AR subtypes or native dopaminergic D₂ receptor was about 100-fold lower than that for alpha-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 confirmed in 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 tissues via activation of the alpha-1L AR. Hence this alpha-1 AR subtype, rather than the alpha-1A AR, may mediate the contraction in vivo.