Synthesis of 4-(aminoalkyl) substituted 1,3-dioxanes as potent NMDA and σ receptor antagonists.
Synthesis of 4-(aminoalkyl) substituted 1,3-dioxanes as potent NMDA and σ receptor antagonists.
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合成 4-（氨基烷基）取代的 1,3-二恶烷作为有效的 NMDA 和 σ 受体拮抗剂。
DOI：
10.1016/j.ejmech.2011.02.070
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发表时间：
2011
影响因子：
6.7
通讯作者：
B. Wünsch
中科院分区：
文献类型：
--
作者：
T. Utech;Jens Köhler;B. Wünsch
NMDA受体拮抗剂地昔沙卓和乙氧沙卓的氧杂环和碱性氨基部分之间的距离的延长或氧杂环的环膨胀导致具有有希望的NMDA受体亲和力的化合物。在本文中，设想了两种结构特征的组合，即O-杂环-胺距离与1，3-二氧杂环己烷环的延长。氨乙基-1，3-二氧六环1,3、22、23和29的合成是通过各种缩醛与戊烷-1，3，5-三醇的转缩醛化、用甲苯磺酰氯活化剩余的游离OH部分和随后的亲核取代来进行的。相应的3-氨基丙基衍生物33 - 35通过用KCN取代甲苯磺酸酯和LiAlH 4还原来制备。最高的NMDA受体亲和力被发现与1，3-二氧杂环己烷与苯基和乙基残基在乙醛酸位置（23），其次是二苯基（22）和单苯基衍生物（13）。通常，伯胺的NMDA亲和力高于仲胺和叔胺的NMDA亲和力。总而言之，伯胺23 a（Ki= 24 nM）代表了该系列中最有前途的NMDA受体拮抗剂，超过了单同系物（2-氨乙基）-1，3-二氧戊环（3，4）和（氨甲基）-1，3-二氧杂环己烷（5，6）的NMDA亲和力。伯胺23对σ 1和σ 2受体具有选择性，而苄胺13 d被鉴定为有效的（Ki= 19 nM）和选择性σ 1拮抗剂，在辣椒素试验中显示出非常高的抗异常性疼痛活性。
Elongation of the distance between the oxygen heterocycle and the basic amino moiety or ring expansion of the oxygen heterocycle of the NMDA receptor antagonists dexoxadrol and etoxadrol led to compounds with promising NMDA receptor affinity. Herein the combination of both structural features, i.e. elongation of the O-heterocycle – amine distance with a 1,3-dioxane ring is envisaged. The synthesis of aminoethyl-1,3-dioxanes13,22,23and29was performed by transacetalization of various acetals with pentane-1,3,5-triol, activation of the remaining free OH moiety with tosyl chloride and subsequent nucleophilic substitution. The corresponding 3-aminopropyl derivatives33–35were prepared by substitution of the tosylates with KCN and LiAlH4reduction. The highest NMDA receptor affinity was found for 1,3-dioxanes with a phenyl and an ethyl residue at the acetalic position (23) followed by diphenyl (22) and monophenyl derivatives (13). Generally the NMDA affinity of primary amines is higher than the NMDA affinity of secondary and tertiary amines. Altogether the primary amine23a(Ki= 24 nM) represents the most promising NMDA receptor antagonist of this series exceeding the NMDA affinity of the mono-homologues (2-aminoethyl)-1,3-dioxolanes (3,4) and (aminomethyl)-1,3-dioxanes (5,6). Whereas the primary amine23aturned out to be selective against σ1and σ2receptors the benzylamine13dwas identified as potent (Ki= 19 nM) and selective σ1antagonist, which showed extraordinarily high antiallodynic activity in the capsaicin assay.
3H-苯环己哌啶在脑膜中的立体特异性结合。
影响因子：
6.1
作者：
Hampton,RY;Medzihradsky,F;Woods,JH;Dahlstrom,PJ
通讯作者：
Dahlstrom,PJ
二氧戊环 dexoxadrol 和 etoxadrol 的类似物作为潜在的苯环己哌啶类药物。
影响因子：
7.3
作者：
Thurkauf,A;Mattson,MV;Richardson,S;Mirsadeghi,S;Ornstein,PL;HarrisonJr,EA;Rice,KC;Jacobson,AE;Monn,JA
通讯作者：
Monn,JA
强效苯环己哌啶类激动剂依托托醇的合成、绝对构型和分子模型研究。
影响因子：
7.3
作者：
Thurkauf,A;Zenk,PC;Balster,RL;May,EL;George,C;Carroll,FI;Mascarella,SW;Rice,KC;Jacobson,AE;Mattson,MV
通讯作者：
Mattson,MV