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Vol. 281, Issue 3, 1272-1283, 1997
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
(Kb = 2-3 nM) being observed in urethra and
prostate, compared with ear artery and aorta
(Kb = 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.
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