1-[1-(2-苯并[b]噻吩基)环己基]哌啶同源物在多巴胺摄取位点和苯环利定与sigma结合位点的合成及生物学评价。

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他XS，雷蒙LP，马特森MV, Eldefrawi ME，德科斯塔BR

1-[1-(2-苯并[b]噻吩基)环己基]哌啶同源物在多巴胺摄取位点和苯环利定与sigma结合位点的合成及生物学评价。

中华医学化学杂志1993 4月30日;36(9):1188-93。

PubMed ID
8098066 (PubMed视图
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摘要

由合适的环烷酮经四步分别制备了高亲和力多巴胺(DA)摄取抑制剂1-[1-(2-苯并[b]噻吩基)环己基]哌啶(BTCP, 3)的环己基环同源物哌啶和环己基环。测试了这些化合物取代[3H]BTCP和[3H]可卡因的能力，并抑制大鼠纹状体匀浆中[3H]DA的摄取。IC50([3H]可卡因)/IC50([3H]BTCP)的比值从BTCP的62到1-[2-(苯并[b]噻吩基)-环戊胺的1.5 (17);可卡因的比率为0.6。这表明BTCP对[3H]BTCP标记位点的选择性最强，而可卡因对[3H]可卡因标记位点的选择性最强。这些化合物取代[3H]BTCP和[3H]可卡因的相对能力存在巨大差异，这表明这两种放射性配基在转运体上标记了不同的位点。总的来说，与BTCP结构相关的化合物对[3H]BTCP标记的位点表现出更高的选择性。然而，几种与BTCP相关的衍生物(与BTCP和可卡因相比)显示出更大的取代[3H]可卡因的能力。最值得注意的是，1-[1-(2-苯并[b]噻吩基)环己基]吡咯烷(7)对这些位点的亲和力比BTCP高3.4倍，比可卡因高9倍。大多数BTCP同源物在大鼠前脑突触体中表现出比可卡因更强的抑制[3H]DA摄取的能力。 BTCP and 7 were the most potent of all the compounds tested in terms of their ability to inhibit uptake of [3H]DA. IC50 ratios for [3H]cocaine binding/[3H]DA uptake ranged from 0.47 for 1-[1-(2-benzo[b]thienyl)cyclopentyl]homopiperidine (11) to 8.8 for 1-(2-benzo[b]thienyl)cyclohexylamine (4). The importance of this ratio remains unclear in terms of identification of potential cocaine antagonists. As for BTCP, all of the compounds tested showed Ki values > 10,000 nM for displacement of [3H]TCP from rat brain homogenates. These compounds were able to displace the highly selective sigma receptor probe [3H]-(+)-pentazocine from guinea pig brain homogenates with Ki values ranging from 125 to 9170 nM. The significance of their sigma-binding activity in light of their dopaminergic properties is unclear. The diverse binding properties of these compounds at the DA-uptake site and their spectrum of inhibitory activities for [3H]DA uptake identifies them as a useful base for the development of subtype selective probes at this site. These compounds will allow further study of the structure and function of the "cocaine" receptor as well as the development of potential cocaine antagonists.

引用本文的药物库数据

绑定属性
药物 目标 财产 测量 pH值 温度(°C)
镇痛新 Sigma非阿片细胞内受体1 Ki (nM) 3.8 N/A N/A 细节
苯环己哌啶 Sigma非阿片细胞内受体1 Ki (nM) 1767 N/A N/A 细节