Lambrecht G, Ganso M, Bäumert H G, Spatz-Kümbel G, Hildebrandt C, Braun K, Mutschler E
Department of Pharmacology, Biocentre Niederursel, University of Frankfurt, Marie-Curie-Str. 9, D-60439, Frankfurt/M., Germany.
J Auton Nerv Syst. 2000 Jul 3;81(1-3):171-7. doi: 10.1016/s0165-1838(00)00135-1.
Effects of 6-[(4,6,8-trisulfo-1-naphthyl)iminocarbonyl-1, 3-(4-methylphenylene)iminocarbonyl-1, 3-phenylene-azo]-pyridoxal-5'-phosphate (SB9), a heterodimeric bivalent ligand consisting of pyridoxal-5'-phosphate and the suramin monomer, were studied on contractions of the rat vas deferens elicited by alpha beta-methylene ATP (alpha beta meATP; mediated by P2X(1)-like receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S mediated by P2Y(1)-like receptors), and the degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. SB9 (0.1-10 microM) antagonized contractile responses produced by alpha beta meATP or ADP beta S in a concentration-dependent manner. Schild analysis yielded linear regression lines of unit slope, indicating competitive antagonism. From the rightward shifts of the agonist concentration-response curves pA(2) values of 6.05+/-0.13 (vas deferens) and 6.98+/-0.07 (ileum) were derived. In both preparations, SB9 behaved as a slow onset, slow offset antagonist. Incubation of three oocytes in the presence of ATP produced an increase in inorganic phosphate (P(i)) over a 30-min period, which amounted to 35.1+/-1.9 microM P(i) from 100 microM ATP. SB9 (10-1000 microM) reduced this degradation (pIC(50)=4.33+/-0.10). The results illustrate that SB9 is a high-affinity P2Y(1) receptor antagonist with a remarkable selectivity for P2Y(1) vs. P2X(1) receptors (about 10-fold) and ecto-nucleotidases (447-fold). These properties make it unique among the pyridoxal-5'-phosphate and suramin derivatives reported to date.
研究了6-[(4,6,8-三磺基-1-萘基)亚氨基羰基-1,3-(4-甲基亚苯基)亚氨基羰基-1,3-亚苯基-偶氮]-吡哆醛-5'-磷酸酯（SB9）对αβ-亚甲基ATP（αβmeATP；由P2X(1)样受体介导）引起的大鼠输精管收缩、5'-O-(2-硫代二磷酸)腺苷（ADPβS，由P2Y(1)样受体介导）引起的豚鼠回肠纵行平滑肌收缩以及卵泡期非洲爪蟾卵母细胞中外核苷酸酶对ATP的降解作用。SB9（0.1 - 10μM）以浓度依赖性方式拮抗αβmeATP或ADPβS产生的收缩反应。Schild分析得出单位斜率的线性回归线，表明为竞争性拮抗作用。从激动剂浓度 - 反应曲线的右移得出输精管的pA(2)值为6.05±0.13，回肠的pA(2)值为6.98±0.07。在两种制剂中，SB9表现为起效缓慢、作用消失缓慢的拮抗剂。在ATP存在下孵育三个卵母细胞30分钟内无机磷酸盐（P(i)）增加，100μM ATP产生的P(i)为35.1±1.9μM。SB9（10 - 1000μM）减少了这种降解（pIC(50)=4.33±0.10）。结果表明，SB9是一种高亲和力的P2Y(1)受体拮抗剂，对P2Y(1)与P2X(1)受体（约10倍）和外核苷酸酶（447倍）具有显著的选择性。这些特性使其在迄今报道的吡哆醛-5'-磷酸酯和苏拉明衍生物中独一无二。
