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

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Abstract

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
Volume127
Issue number1
DOIs
Publication statusPublished - 18 May 1999
Externally publishedYes

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tamsulosin
Adrenergic Receptors
Prazosin
Pharmacology
Urinary Tract
Prostatic Hyperplasia
Renal Artery
Aorta
CHO Cells
Second Messenger Systems
Ro 70-0004
RS 100329
In Vitro Techniques
Norepinephrine
Urinary Bladder
Rabbits

Cite this

Williams, T. J., Blue, D. R., Daniels, D. V., Davis, B., Elworthy, T., Gever, J. R., ... 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. https://doi.org/10.1038/sj.bjp.0702541
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. / In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α(1A)-adrenoceptor selective antagonists. In: British Journal of Pharmacology. 1999 ; Vol. 127, No. 1. pp. 252-258.
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title = "In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α(1A)-adrenoceptor selective antagonists",
abstract = "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.",
author = "Williams, {T. J.} and Blue, {D. R.} and Daniels, {D. V.} and B. Davis and T. Elworthy and Gever, {J. R.} and Kava, {M. S.} and D. Morgans and F. Padilla and S. Tassa and Vimont, {R. L.} and Chapple, {C. R.} and R. Chess-Williams and Eglen, {R. M.} and Clarke, {D. E.} and Ford, {A. P.D.W.}",
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Williams, TJ, Blue, DR, Daniels, DV, Davis, B, Elworthy, T, Gever, JR, Kava, MS, Morgans, D, Padilla, F, Tassa, S, Vimont, RL, Chapple, CR, Chess-Williams, R, Eglen, RM, Clarke, DE & Ford, APDW 1999, 'In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α(1A)-adrenoceptor selective antagonists' British Journal of Pharmacology, vol. 127, no. 1, pp. 252-258. https://doi.org/10.1038/sj.bjp.0702541

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

In: British Journal of Pharmacology, Vol. 127, No. 1, 18.05.1999, p. 252-258.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α(1A)-adrenoceptor selective antagonists

AU - Williams, T. J.

AU - Blue, D. R.

AU - Daniels, D. V.

AU - Davis, B.

AU - Elworthy, T.

AU - Gever, J. R.

AU - Kava, M. S.

AU - Morgans, D.

AU - Padilla, F.

AU - Tassa, S.

AU - Vimont, R. L.

AU - Chapple, C. R.

AU - Chess-Williams, R.

AU - Eglen, R. M.

AU - Clarke, D. E.

AU - Ford, A. P.D.W.

PY - 1999/5/18

Y1 - 1999/5/18

N2 - 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.

AB - 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.

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