Tj. Williams et al., In vitro alpha(1)-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha(1A)-adrenoceptor selective antagonists, BR J PHARM, 127(1), 1999, pp. 252-258
1 It has been hypothesized that in patients with benign prostatic hyperplas
ia, selective antagonism of the alpha(1A)-adrenoceptor-mediated contraction
of lower urinary tract tissues may, via a selective relief of outlet obstr
uction, lead to an improvement in symptoms.
2 The present study describes the alpha(1)-adrenoceptor (alpha(1)-AR) subty
pe selectivities of two novel alpha(1)-AR antagonists, Ro 70-0004 (aka RS-1
00975) and a structurally-related compound RS-100329, and compares them wit
h those of prazosin and tamsulosin. Radioligand binding and second-messenge
r studies in intact CHO-KI cells expressing human cloned alpha(1A)-, alpha(
1B)- and alpha(1D)-AR showed nanomolar affinity and significant alpha(1A)-A
R subtype selectivity for both Ro 70-0004 (pK(i) 8.9: 60 and 50 fold select
ivity) and RS-100329 (pK(i) 9.6: 126 and 50 fold selectivity) over the alph
a(1B)- and alpha(1D)-AR subtypes respectively. In contrast, prazosin and ta
msulosin showed little subtype selectivity.
3 Noradrenaline-induced contractions of human lower urinary tract (LUT) tis
sues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (p
A(2) 8.8 and 8.9), RS-100329 (pA(2) 9.2 and 9.2), tamsulosin (pA(2) 10.4 an
d 9.8) and prazosin (pA(2) 8.7 and 8.3 respectively). Affinity estimates fo
r tamsulosin and prazosin in antagonizing alpha(1)-AR-mediated contractions
of human renal artery (HRA) and rat aorta (RA) were similar to those obser
ved in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100
fold less potent (pA(2) values of 6.8/6.8 and 7.3/7.9 in HRA/RA respective
ly).
4 The alpha(1A)-AR subtype selectivity of Ro 70-0004 and RS-100329, demonst
rated in both cloned and native systems, should allow for an evaluation of
the clinical utility of a 'uroselective' agent for the treatment of symptom
s associated with benign prostatic hyperplasia.