Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs)
Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs)
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DOI：
10.1016/s0968-0896(97)00111-9
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发表时间：
1997-08-01
影响因子：
3.5
通讯作者：
Razdan, RK
中科院分区：
文献类型：
--
作者：
Dutta, AK;Ryan, W;Razdan, RK
以4-苄氧基吲哚（1）为原料，合成了几种新的4-烷氧基氨烷基吲哚衍生物3。用4-（2-氯乙基）吗啉（NaH/HMPA）烷基化1形成2。使用氢氧化钯在碳/氢上脱保护，然后用适当的烷基溴烷基化，得到目标化合物3b-3 j。在3 i和3 j的合成中，使用如方案3所示的链延长顺序，由市售的1-萘乙基溴9制备适当的烷基溴13和17。在受体结合测定和体内测试中，长链烷氧基化合物3g和3 h（Ki = 127 nM）显示出对CB 1受体的亲和力，其比WIN 55，225的亲和力低约16-35倍。然而，3 h的药理学特征与WIN 55，212相似。对这些类似物的SAR的检查表明，通过氧（醚键）将AAI中的萘基从C-3位置转移到C-4位置会降低活性，这与先前的发现（C-4处的萘基羰基保留活性）相反。目前的工作点的重要性，酮基的作用与受体的相互作用。分子模拟工作表明，尽管可以在Delta（9）-THC和AAI之间进行关键结构特征的合理叠加，但叠加并不简单。本研究还说明了将AAI纳入大麻素药效团的困难，似乎需要开发一种独特的药效团。只有这样，与经典大麻素药效团的相似性和差异才能清楚地描述出来。(C)1997 Elsevier Science Ltd.
Several novel 4-alkyloxy-aminoalkyl indole derivatives 3 were synthesized from 4-benzyloxyindole (1). Alkylation of 1 with 4-(2-chloroethyl)morpholine (NaH/HMPA) formed 2. Deprotection using palladium hydroxide on carbon/hydrogen followed by alkylation with the appropriate alkyl bromide gave the target compounds 3b-3j. In the synthesis of 3i and 3j, the appropriate alkyl bromides 13 and 17 were prepared from the commercially available 1-naphthylethyl bromide 9 using the chain lengthening sequences as shown in Scheme 3. In receptor binding assay and in vivo testing, the long chain alkoxy compounds 3g and 3h (K-i = 127 nM) showed affinity for the CB1 receptor which was approximately 16-35-fold less than that of WIN 55,225. However, the pharmacological profile of 3h mimics that of WIN 55,212. An examination of the SAR of these analogues shows that translocating the napthyl group in AAIs from the C-3 position to C-4 via an oxygen (ether linkage) decreases activity which is in contrast to previous findings that a naphthylcarbonyl at C-4 retains activity. The present work points to the importance of the role of a keto group in the interaction with the receptor. Molecular modeling work suggests that, although reasonable superposition of key structural features between Delta(9)-THC and AAIs can be made, the overlay is not straightforward. The present study also illustrates the difficulty in accommodating AAIs into the cannabinoid pharmacophore and it seems likely that a unique pharmacophore will need to be developed. Only then will the similarities to and differences from the classical cannabinoid pharmacophore be clearly delineated. (C) 1997 Elsevier Science Ltd.