Molecular basis of peripheral vs central benzodiazepine receptor selectivity in a new class of peripheral benzodiazepine receptor ligands related to alpidem
Molecular basis of peripheral vs central benzodiazepine receptor selectivity in a new class of peripheral benzodiazepine receptor ligands related to alpidem
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DOI：
10.1021/jm960325j
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发表时间：
1996-10-11
影响因子：
7.3
通讯作者：
Basile, AS
中科院分区：
文献类型：
--
作者：
Anzini, M;Cappelli, A;Basile, AS
Alpidem(1)是一种抗焦虑的咪唑吡啶，对中枢苯二氮卓受体（CBR）和外周苯二氮卓受体（PER）都具有纳米摩尔结合亲和力。通过比较alpidem与PER和CBR的相互作用模型，设计了一类新的与alpidem相关的PER配体。这类化合物中有几种对PER和CBR表现出较高的选择性，并根据相互作用模型讨论了这种选择性。通过竞争和饱和实验广泛研究了这三种选定化合物的结合行为，结果表明它们能够识别[H-3]PK11195标记的两个位点。用x射线衍射测定了其中最活跃的化合物（4e）的分子结构，并与alpidem的分子结构进行了比较。分子模拟研究表明，4e的生物活性构象可能与晶体中的构象非常相似。
Alpidem (1), the anxiolytic imidazopyridine, has nanomolar binding affinity for both the central benzodiazepine receptor (CBR) and the peripheral benzodiazepine receptor (PER). A novel class of PER ligands related to alpidem has been designed by comparing the interaction models of alpidem with PER and CBR. Several compounds in this class have shown high selectivity for PER vs CBR, and the selectivity has been discussed in terms of interaction models. The binding behavior of the three selected compounds was extensively studied by competition and saturation assays, and the results suggest that they are capable of recognizing two sites labeled by [H-3]PK11195. The molecular structure of one of the most active compounds (4e) has been determined by X-ray diffraction and compared with that of alpidem. Molecular modeling studies suggest that the bioactive conformation of 4e is Likely to be very similar to the conformation found in the crystal.