Structure-activity relationships of pyridoxal phosphate derivatives as potent and selective antagonists of P2X1 receptors
Structure-activity relationships of pyridoxal phosphate derivatives as potent and selective antagonists of P2X1 receptors
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DOI：
10.1021/jm9904203
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发表时间：
2001-02-01
影响因子：
7.3
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Kim, YC;Brown, SG;Jacobson, KA
合成了P2受体拮抗剂吡啶多醛-5′-磷酸6-偶氮酰基-2′，5′-二磺酸盐(2)的新型类似物，并在重组大鼠P2X(1)、P2X(2)和P2X(3)受体(爪蟾卵母细胞（狮子通量刺激）和火鸡红细胞P2Y(1)受体（磷脂酶C激活）的功能测定中作为拮抗剂进行了研究。选定的化合物也被评价为离子通量拮抗剂和重组人P2X(7)受体上打开大孔的拮抗剂。对吡哆醛部分的4-醛和5'-磷酸基团进行了修饰：即吡哆醇中4位的CH2OH基团凝聚成环磷酸或单独磷酸化形成二磷酸，从而降低了对P2受体的效价。5-甲基膦酸盐取代，预期增加水解稳定性，保留P2受体效力。在g位，苯基偶氮环上的光环、羧酸盐、磺酸盐和膦酸盐的变化调节了P2受体的效价。磷酸2的对羧基苯基偶氮类似物4在重组P2X(1)受体上的IC50值为9 nM，对P2X(1)与P2X(2)、P2X(3)和P2Y(1)亚型的选择性分别为1300-、16-和100万倍。相应的ei -甲基膦酸盐在P2X(1)受体上具有同等效力。5-甲基膦酸盐类似物含有6-[3,5-双（甲基膦酸盐）]苯基偶氮片段9，在重组P2X(1)和P2X(3)受体上的IC50值分别为11和25 nM。含有苯基偶氮- 4-膦酸基团的类似物11，在P2X(1)和P2X(3)受体上也非常有效。然而，相应的2,5-二磺酸盐类似物10对P2X(1)受体的选择性是P2X(3)受体的28倍。没有一个类似物在P2X(7)和P2Y(1)受体上比2更有效，这两个亚型在微摩尔范围内起作用。
Novel analogues of the P2 receptor antagonist pyridoxal-5'-phosphate 6-azophcnyl-2',5'-disulfonate (2) were synthesized and studied as antagonists in functional assays at recombinant rat P2X(1), P2X(2), and P2X(3) receptors expressed in Xenopus oocytes lion flux stimulation) and at turkey erythrocyte P2Y(1) receptors (phospholipase C activation). Selected compounds were also evaluated as antagonists of ion flux and the opening of a large pore at the recombinant human P2X(7) receptor. Modifications were made in the 4-aldehyde and 5'-phosphate groups of the pyridoxal moiety: i.e. a CH2OH group at the 4-position in pyridoxine was either condensed as a cyclic phosphate or phosphorylated separately to form a bisphosphate, which reduced potency at P2 receptors. 5-Methylphosphonate substitution, anticipated to increase stability to hydrolysis, preserved P2 receptor potency. At the g-position, halo, carboxylate, sulfonate, and phosphonate variations made on the phenylazo ring modulated potency at P2 receptors. The p-carboxyphenylazo analogue, 4, of phosphate 2 displayed an IC50 value of 9 nM at recombinant P2X(1) receptors and was 1300-, 16-, and >10000-fold selective for P2X(1) versus P2X(2), P2X(3), and P2Y(1) subtypes, respectively. The corresponding Ei-methylphosphonate was equipotent at P2X(1) receptors. The 5-methylphosphonate analogue containing a 6-[3,5-bis(methylphosphonate)]phenylazo moiety, 9, had IC50 values of 11 and 25 nM at recombinant P2X(1) and P2X(3) receptors, respectively. The analogue containing a phenylazo 4-phosphonate group, 11, was also very potent at both P2X(1) and P2X(3) receptors. However, the corresponding 2,5-disulfonate analogue, 10, was 28-fold selective for P2X(1) versus P2X(3) receptors. None of the analogues were more potent at P2X(7) and P2Y(1) receptors than 2, which acted in the micromolar range at these two subtypes.