Tuluc F, Bültmann R, Glänzel M, Frahm A W, Starke K
Pharmakologisches Institut, Freiburg i. Br., Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Feb;357(2):111-20. doi: 10.1007/pl00005144.
Effects of reactive blue 2 and twelve structurally related compounds were studied on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alpha,beta-MeATP; mediated by P2X-receptors), relaxations of the carbachol-precontracted guinea-pig taenia coli elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS; mediated by P2Y-receptors), and the degradation of ATP by rat vas deferens tissue. All compounds, except acid blue 41 and acid blue 129 (at up to 100 microM), shifted the concentration-response curve of alpha,beta-MeATP in the rat vas deferens to the right. Most increased, but uniblue A greatly decreased, the maximum of the curve. In the case of cibacron blue 3GA and reactive blue 19, of which three concentrations were tested, the Arunlakshana-Schild regression was linear, and the slope did not differ from unity. The apparent Kd values of the effective substances ranged between 0.7 and 111 microM. Most compounds increased the contraction of the rat vas deferens elicited by high K+. In the guinea-pig taenia coli, all compounds, except uniblue A and reactive blue 19 (at up to 100 microM), shifted the concentration-response curve of ADPbetaS to the right in a parallel manner. In the case of acid blue 129 and acid blue 80, of which three concentrations were tested, the slope of the Arunlakshana-Schild regression did not differ from unity. The apparent Kd values of the effective substances were between 0.7 and 69 microM. Most compounds also reduced the relaxation of the guinea-pig taenia coli elicited by noradrenaline. The removal of ATP from the medium by vas deferens tissue was decreased only by reactive blue 2, cibacron blue 3GA, uniblue A and reactive blue 19, with IC25% values between 17 and 62 microM. The structure-activity relationships for P2X- and P2Y-receptor blockade in this series are strikingly dissimilar. In reactive blue 2 and its isomers, for example, both the 1-amino-anthraquinone-2-sulphonate core and the 'side-chain' of the molecule are involved in P2X-receptor binding; P2Y-receptor affinity, in contrast, resides largely or totally in the anthraquinone core. The most promising antagonists are uniblue A which is P2X- versus P2Y-selective and acid blue 129 which is P2Y- versus P2X-selective, both with few, if any, non-P2-receptor effects at concentrations blocking the respective P2-subtype.
研究了活性蓝2及12种结构相关化合物对α,β-亚甲基ATP（α,β-MeATP；由P2X受体介导）诱发的大鼠输精管收缩、5'-O-(2-硫代二磷酸)腺苷（ADPβS；由P2Y受体介导）诱发的豚鼠结肠带由卡巴胆碱预收缩后的松弛，以及大鼠输精管组织中ATP降解的影响。除酸性蓝41和酸性蓝129（浓度高达100μM时）外，所有化合物均使大鼠输精管中α,β-MeATP的浓度-反应曲线右移。大多数化合物使曲线的最大值增加，但单蓝A使其大幅降低。对于测试了三种浓度的汽巴克隆蓝3GA和活性蓝19，阿仑拉克沙纳-席尔德回归呈线性，斜率与1无差异。有效物质的表观Kd值在0.7至111μM之间。大多数化合物增加了高钾诱发的大鼠输精管收缩。在豚鼠结肠带中，除单蓝A和活性蓝19（浓度高达100μM时）外，所有化合物均以平行方式使ADPβS的浓度-反应曲线右移。对于测试了三种浓度的酸性蓝129和酸性蓝80，阿仑拉克沙纳-席尔德回归的斜率与1无差异。有效物质的表观Kd值在0.7至69μM之间。大多数化合物还降低了去甲肾上腺素诱发的豚鼠结肠带的松弛。仅活性蓝2、汽巴克隆蓝3GA、单蓝A和活性蓝19可降低输精管组织从培养基中去除ATP的能力，其IC25%值在17至62μM之间。该系列中P2X和P2Y受体阻断的构效关系明显不同。例如，在活性蓝2及其异构体中，1-氨基蒽醌-2-磺酸盐核心和分子的“侧链”均参与P2X受体结合；相比之下，P2Y受体亲和力主要或完全存在于蒽醌核心中。最有前景的拮抗剂是对P2X与P2Y具有选择性的单蓝A和对P2Y与P2X具有选择性的酸性蓝129，在阻断各自P2亚型的浓度下，二者几乎没有非P2受体效应（如果有的话）。
