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首页> 外文期刊>Journal of Heterocyclic Chemistry: The International Journal of Heterocyclic Chemistry >Synthesis of N-substituted piperidine salts as potential muscarinic ligands for Alzheimer's applications
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Synthesis of N-substituted piperidine salts as potential muscarinic ligands for Alzheimer's applications

机译：N-取代的哌啶盐的合成作为潜在的毒蕈碱配体，可用于阿尔茨海默病的应用

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摘要

Several heterocyclic N-piperidine substituted salts were synthesized that were found to inhibit the specific binding of the antagonist [~3H] quinuclidinyl benzilate in radioligand muscarinic binding assays (~3H-QNB) in bioassays. One of the heterocyclic salts, compound 7, met the significance criteria in these assays (>50% inhibition) at 10 μM of the nonselective muscarinic antagonist (~3H-QNB) in cells of the Wistar rat cerebral cortex. Furthermore, this compound displayed 61% inhibition at 10 μM of the antagonist (~3H-QNB) for the M_5 receptor (IC_(50) 6.34 μM, K_i 3.93 μM, n_H = 0.996) in human recombinant CHO cell lines. These data obtained from Ricerca Biosciences suggested that compound 7 was selective for the M_5 receptor. Another study from the Czech Academy of Sciences demonstrated that compound 7 was 3 to 8 times more potent at M_2 than other subtypes of muscarinic receptors in competition with antagonist N-methylscopolamine and selective for the M_1 receptors over M_3 and M_5 in antagonizing accumulation of inositol phosphates induced by muscarinic agonist carbachol.
机译：合成了几种杂环N-哌啶取代的盐，这些盐在生物测定的放射性配体毒蕈碱结合测定（〜3H-QNB）中被发现能抑制拮抗剂[〜3H]奎宁环基苯甲酸酯的特异性结合。在这些测定中，一种杂环盐化合物7在Wistar大鼠大脑皮层细胞中的非选择性毒蕈碱拮抗剂（〜3H-QNB）浓度为10μM时，在这些测定中符合显着性标准（抑制> 50％）。此外，该化合物在人重组CHO细胞系中对M_5受体（IC_（50）6.34μM，K_i 3.93μM，n_H = 0.996）的拮抗剂（〜3H-QNB）在10μM处显示61％的抑制作用。从Ricerca Biosciences获得的这些数据表明，化合物7对M_5受体具有选择性。捷克科学院的另一项研究表明，与拮抗N-甲基东other碱竞争，化合物7在M_2上的毒力比其他毒蕈碱受体亚型高3至8倍，并且在拮抗肌醇磷酸盐积累方面对M_1和M_5的M_1受体具有选择性由毒蕈碱激动剂卡巴胆碱诱导。

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