SEARCH FOR THE PHARMACOPHORE OF BISPYRIDINIUM-TYPE ALLOSTERIC MODULATORS OF MUSCARINIC RECEPTORS
SEARCH FOR THE PHARMACOPHORE OF BISPYRIDINIUM-TYPE ALLOSTERIC MODULATORS OF MUSCARINIC RECEPTORS
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DOI：
10.1021/jm00036a008
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发表时间：
1994-05-13
影响因子：
7.3
通讯作者：
TRANKLE, C
中科院分区：
文献类型：
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作者：
CID, MHB;HOLZGRABE, U;TRANKLE, C
双吡啶肟TMB-4的双(二氯苯基)醚稳定拮抗剂与M(2)-胆碱受体的结合，这表明它具有变构作用。合成了10多个该先导化合物的衍生物以研究其构效关系。化合物的变构效力由使猪心脏胆碱能受体上的[H-3]N-甲基东莨菪胺的解离速率减慢2倍的浓度来表示(EC(50))。与TMB-4相比，双(二氯苯基)衍生物4a的效价提高了200多倍(EC(50)=4.7um M)。二氯苯基中的一个可以被甲基取代而不会失去活性(EC(50)=4.5µM)。分子这一端的进一步缩短伴随着效价的适度下降，最低EC(50)=26微米。第二季铵不是变构活性的先决条件。结果表明，一半的先导化合物与M(2)-胆碱受体的变构中心相互作用是关键的，而分子的另一端调节变构活性。
The bis(dichlorobenzyl) ether of the bispyridinium oxime TMB 4 stabilizes antagonist binding to M(2)-cholinoceptors which is indicative of an allosteric action. More than 10 derivatives of the lead compound were synthesized to investigate structure-activity relationships. The allosteric potency of the compounds was indicated by the concentrations which retarded the rate of dissociation of [H-3]N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC(50)). Compared with TMB 4, the bis(dichlorobenzyl) derivative 4a displayed a more than 200-fold higher potency (EC(50) = 4.7 mu M). One of the dichlorobenzyl groups could be replaced by a methyl group without loss of activity (EC(50) = 4.5 mu M). Further shortening of this end of the molecule was accompanied by a moderate decline in potency to a minimum of EC(50) = 26 mu M. The second quaternary nitrogen was not a prerequisite for an allosteric activity. It is concluded that one half of the lead compound is pivotal for an interaction with the allosteric site of the M(2)-cholinoceptor, whereas the opposite end of the molecule modulates the allosteric activity.