In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α(1A)-adrenoceptor selective antagonists

T. J. Williams*, D. R. Blue, D. V. Daniels, B. Davis, T. Elworthy, J. R. Gever, M. S. Kava, D. Morgans, F. Padilla, S. Tassa, R. L. Vimont, C. R. Chapple, R. Chess-Williams, R. M. Eglen, D. E. Clarke, A. P.D.W. Ford

*Corresponding author for this work

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1. It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the α(1A)-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. 2. The present study describes the α1-adrenoceptor (α1-AR) subtype selectivities of two novel α1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned α(1A)-, α(1B)- and α(1D)-AR showed nanomolar affinity and significant α(1A)-AR subtype selectivity for both Ro 70-0004 (pK(i) 8.9: 60 and 50 fold selectivity) and RS-100329 (pK(i) 9.6: 126 and 50 fold selectivity) over the α(1B)- and α(1D)-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. 3. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing α1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). 4. The α(1A)-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.

Original languageEnglish
Pages (from-to)252-258
Number of pages7
JournalBritish Journal of Pharmacology
Issue number1
Publication statusPublished - 18 May 1999
Externally publishedYes

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    Williams, T. J., Blue, D. R., Daniels, D. V., Davis, B., Elworthy, T., Gever, J. R., Kava, M. S., Morgans, D., Padilla, F., Tassa, S., Vimont, R. L., Chapple, C. R., Chess-Williams, R., Eglen, R. M., Clarke, D. E., & Ford, A. P. D. W. (1999). In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α(1A)-adrenoceptor selective antagonists. British Journal of Pharmacology, 127(1), 252-258.