Premium
In vitro α 1 ‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α 1A ‐adrenoceptor selective antagonists
Author(s) -
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,
ChessWilliams R,
Eglen R M,
Clarke D E,
Ford A P D W
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702541
Subject(s) - pharmacology , adrenergic receptor , in vitro , antagonist , chemistry , medicine , receptor , endocrinology , biochemistry
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. The present study describes the α 1 ‐adrenoceptor (α 1 ‐AR) subtype selectivities of two novel α 1 ‐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. Noradrenaline‐induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70‐0004 (pA 2 8.8 and 8.9), RS‐100329 (pA 2 9.2 and 9.2), tamsulosin (pA 2 10.4 and 9.8) and prazosin (pA 2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing α 1 ‐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 (pA 2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). 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.British Journal of Pharmacology (1999) 127 , 252–258; doi: 10.1038/sj.bjp.0702541