THE SYNTHESIS OF NOVEL GABA UPTAKE INHIBITORS .1. ELUCIDATION OF THE STRUCTURE-ACTIVITY STUDIES LEADING TO THE CHOICE OF (R)-1-[4,4-BIS(3-METHYL-2-THIENYL)-3-BUTENYL]-3-PIPERIDINECARBOXYLIC ACID (TIAGABINE) AS AN ANTICONVULSANT DRUG CANDIDATE
THE SYNTHESIS OF NOVEL GABA UPTAKE INHIBITORS .1. ELUCIDATION OF THE STRUCTURE-ACTIVITY STUDIES LEADING TO THE CHOICE OF (R)-1-[4,4-BIS(3-METHYL-2-THIENYL)-3-BUTENYL]-3-PIPERIDINECARBOXYLIC ACID (TIAGABINE) AS AN ANTICONVULSANT DRUG CANDIDATE
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DOI：
10.1021/jm00064a005
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发表时间：
1993-06-11
影响因子：
7.3
通讯作者：
KNUTSEN, LJS
中科院分区：
文献类型：
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作者：
ANDERSEN, KE;BRAESTRUP, C;KNUTSEN, LJS
描述了一系列不同的合成方法，以新颖的GABA摄取抑制剂，导致的例子，这是nipecotic酸和guvacine的衍生物，在氮上取代的4，4-二芳基-3-丁烯基或2-（二苯基甲氧基）乙基部分。测定每种化合物在大鼠突触体中抑制[H-3]-GABA摄取的体外值。发现最有效的实例是在一个或两个芳族/杂芳族基团中的“邻”位具有取代基的那些。描述的大多数化合物在结构上与噻加宾（R）-1-[4，4-双（3-甲基-2-噻吩基）-3-丁烯基]-3-哌啶羧酸盐酸盐（NNC 05-0328）相关，总结了选择该化合物作为候选药物的一些理由。
A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties. The in vitro value for inhibition of [H-3]-GABA uptake in rat synaptosomes was determined for each compound. It was found that the most potent examples are those having a substituent in an ''ortho'' position in one or both aromatic/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.