Novel Potent N-Methyl-D-aspartate (NMDA) Receptor Antagonists or σ1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring
Novel Potent N-Methyl-D-aspartate (NMDA) Receptor Antagonists or σ1 Receptor Ligands Based on Properly Substituted 1,4-Dioxane Ring
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DOI：
10.1021/acs.jmedchem.5b01214
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发表时间：
2015-11-12
影响因子：
7.3
通讯作者：
Quaglia, Wilma
中科院分区：
文献类型：
--
作者：
Bonifazi, Alessandro;Del Bello, Fabio;Quaglia, Wilma
合理设计并制备了两个系列的1，4-二氧六环（4-11和12-19），分别与N-甲基-D-天冬氨酸（NMDA）受体的苯环己哌啶（PCP）结合位点或sigma（1）受体相互作用。使用放射性配体结合试验评估了新化合物的生物学特性，并研究了具有最高亲和力的化合物的功能活性。结果与可用的药效团模型一致，并强调了1，4-二氧六环支架与NMDA受体的有效拮抗剂活性或对sigma（1）受体的高亲和力相容。在6位分别带有环己基和苯环或两个苯环的伯胺6 b和7是NMDA受体的最有效的非竞争性拮抗剂，其IC 50值与解离麻醉剂（S）-（+）-氯胺酮的IC 50值相似。与2位的苄基氨基甲基部分相关的5，5-二苯基取代，如在18中，有利于与sigma（1）受体的相互作用。
Two series of 1,4-dioxanes (4-11 and 12-19) were rationally designed and prepared to interact either with the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor or with sigma(1) receptors, respectively. The biological profiles of the novel compounds were assessed using radioligand binding assays, and the compounds with the highest affinities were investigated for their functional activity. The results were in line with the available pharmacophore models and highlighted that the 1,4-dioxane scaffold is compatible with potent antagonist activity at NMDA receptor or high affinity for sigma(1) receptors. The primary amines 6b and 7 bearing a cyclohexyl and a phenyl ring or two phenyl rings in position 6, respectively, were the most potent noncompetitive antagonists at the NMDA receptor with IC50 values similar to those of the dissociative anesthetic (S)-(+)-ketamine. The 5,5-diphenyl substitution associated with a benzylaminomethyl moiety in position 2, as in 18, favored the interaction with sigma(1) receptors.