Potent 4-aryl- or 4-arylalkyl-substituted 3-isoxazolol GABAA antagonists:: Synthesis, pharmacology, and molecular modeling
Potent 4-aryl- or 4-arylalkyl-substituted 3-isoxazolol GABAA antagonists:: Synthesis, pharmacology, and molecular modeling
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DOI：
10.1021/jm049256w
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发表时间：
2005-01-27
影响因子：
7.3
通讯作者：
Liljefors, T
中科院分区：
文献类型：
--
作者：
Frolund, B;Jensen, LS;Liljefors, T
我们之前已经描述了一系列竞争性的GABA(A)拮抗剂，来自低效的部分激动剂5-(4-哌啶基)-3-异恶唑醇(4-Piol，4)。2-萘甲基类似物4-(2-naphthylmethyl)-5-(4-piperidyl)-3-isoxazolol(5)对GABAA(A)受体的亲和力高于标准GABAA受体拮抗剂SR 95531(3)。这些化合物的分子模拟研究显示，在受体识别位置有一个空洞，能够容纳3-异恶唑环4-位上相当大的芳香基团，这里我们提供了一系列5的类似物，在萘环体系(6a-k)的不同位置有不同的取代基，以及芳香取代基直接连接到3-异恶唑环的4-位的化合物(71-n)。利用受体结合分析和电生理全细胞膜片钳技术对化合物进行了药理学表征。所有被测试的化合物都显示出对GABA(A)受体位点的亲和力。5-、7-和8-溴类似物6b-d的受体亲和力(K-I分别为45、109和80 nM)与5(Ki 49 NM)相当，而1-溴类似物6a的受体亲和力最高(Ki 10 NM)。在2-萘环体系的1-位引入了一系列不同的取代基，从而得到了化合物。6、e-k.与GABA(A)受体保持高亲和力(K-I=16-250 nm)。将苯环直接引入3-异恶唑环上的4-位，亲和力是4-Piol的41倍。在培养的大脑皮层神经元的全细胞膜片钳记录中。所有受试化合物均能抑制GABA(A)激动剂异古卡因的作用，6a的拮抗力(IC50=42 nM)明显高于3(IC50=240 nM)。基于所描述的化合物的分子模拟研究强调了5中的远端环对于受体亲和力的重要性以及所建议的受体腔的相当大的尺寸。此外，根据药效团模型，71和6K中的苯环表示在以前未探索的受体区域中芳环的高度有利位置。
We have previously described a series of competitive GABA(A) antagonists derived from the low-efficacy partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 4). The 2-naphthylmethyl analogue, 4-(2-naphthylmethyl)-5-(4-piperidyl)-3-isoxazolol (5), provided affinity for the GABA(A) receptor site higher than that of the standard GABA(A) receptor antagonist, SR 95531 (3). Molecular modeling studies of these compounds exposed a cavity at the receptor recognition site capable of accommodating aromatic groups of substantial size in the 4-position in the 3-isoxazolol ring, Here we present a series of analogues of 5, with various substituents in different positions in the naphthyl ring system (6a-k), and compounds with aromatic substituents directly attached to the 4-position of the 3-isoxazolol ring (7l-n). The compounds have been pharmacologically characterized using receptor-binding assays and electrophysiological whole-cell patch-clamp techniques. All of the tested compounds show affinity for the GABA(A) receptor site. While the 5-, 7-, and 8-bromo analogues, 6b-d, showed receptor affinities (K-i = 45, 109, and 80 nM, respectively) comparable with that of 5 (Ki 49 nM), the 1-bromo analogue, 6a, provided the highest receptor affinity of the series (Ki 10 nM). Introduction of a series of different substituents in the 1-position in the 2-naphthyl ring system led to compounds. 6,e-k. with retained high affinity for the GABA(A) receptor (K-i = 16-250 nM). Introduction of a phenyl ring directly into the 4-position on the 3-isoxazolol ring gave a 41-fold increase in affinity relative to that of 4-PIOL. In whole-cell patch-clamp recordings from cultured cerebral cortical neurons. all of the tested compounds were able to inhibit the effect of the Specific GABA(A) agonist, isoguvacine, 6a showing antagonist potency (IC50 = 42 nM) markedly higher than that, of 3 (IC50 = 240 nM). Molecular modeling studies, based on the compounds described, emphasized the importance of the distal ring in 5 for receptor affinity and the considerable dimensions of the proposed receptor cavity. Furthermore, the phenyl rings in 71 and in 6k were shown to represent highly favorable positions for an aromatic ring in previously unexplored receptor regions in terms of a pharmacophore model.