In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.
In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.
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Ro 70-0004 和 RS-100329（新型 α1A-肾上腺素受体选择性拮抗剂）的体外 α1-肾上腺素受体药理学。
DOI：
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发表时间：
1999
影响因子：
7.3
通讯作者：
A. Ford
中科院分区：
文献类型：
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作者：
T. Williams;D. Blue;D. V. Daniels;B. Davis;T. Elworthy;J. Gever;M. Kava;D. Morgans;F. Padilla;S. Tassa;R. Vimont;C. Chapple;R. Chess;R. Eglen;D. Clarke;A. Ford
据推测，在良性前列腺增生患者中，选择性拮抗α -肾上腺素能介导的下尿路组织收缩可能通过选择性解除出口阻塞而导致症状改善。本研究描述了两种新型α 1- ar拮抗剂Ro 70-0004（又名RS-100975）和结构相关化合物RS-100329的α 1-肾上腺素受体（alpha1-AR）亚型选择性，并将它们与普拉唑嗪和坦索罗辛进行了比较。在表达人克隆alpha1A-、alpha1B-和alpha1D-AR的完整CHO-K1细胞中进行的辐射配体结合和第二信使研究显示，r70 -0004 （pKi 8.9: 60和50倍选择性）和RS-100329 （pKi 9.6: 126和50倍选择性）对alpha1B-和alpha1D-AR亚型分别具有纳米级亲和力和显著的α 1a - ar亚型选择性。而吡唑嗪和坦索罗辛的亚型选择性较弱。Ro 70-0004 （pA2 8.8和8.9）、RS-100329 （pA2 9.2和9.2）、坦索罗辛（pA2 10.4和9.8）和吡唑嗪（pA2 8.7和8.3）竞争性拮抗去甲肾上腺素诱导的人下尿路组织或兔膀胱颈收缩。坦索罗辛和吡唑嗪对α 1- ar介导的人肾动脉（HRA）和大鼠主动脉（RA）收缩的拮抗作用与LUT组织相似，而Ro 70-0004和RS-100329的效价约低100倍（HRA /RA的pA2值分别为6.8/6.8和7.3/7.9）。Ro 70-0004和RS-100329的α 1a - ar亚型选择性，在克隆和原生系统中都得到了证实，应该允许评估“泌尿选择性”药物治疗良性前列腺增生相关症状的临床效用。
It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-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 alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-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 alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-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 (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 alpha1-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). The alpha1A-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.