Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists
Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists
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DOI：
10.1021/jm980363y
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发表时间：
1999-02-25
影响因子：
7.3
通讯作者：
Makriyannis, A
中科院分区：
文献类型：
--
作者：
Lan, RX;Liu, Q;Makriyannis, A
作为脑大麻素受体（CB 1）的强效特异性拮抗剂，联芳基吡唑N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺（SR 141716 A; 1）是用于启动研究的先导化合物，旨在检查相关化合物的构效关系，并寻找更具选择性和强效的大麻模拟物配体。设计并合成了一系列吡唑衍生物，以帮助表征大麻素受体结合位点，并作为潜在有用的药理学探针。在治疗上，这样的化合物可以具有拮抗大麻素和大麻模拟剂的有害副作用的能力。有效的和选择性的脑大麻素CB 1受体拮抗活性的结构要求包括（a）在5位的对位取代的苯环，（B）在3位的甲酰胺基，和（c）在吡唑环的1位的2，4-二氯苯基取代基。该系列中最有效的化合物在吡唑环的5-位上含有对碘苯基，在S-位上含有哌啶基甲酰胺，在1-位上含有2，4-二氯苯基。该化合物的碘化性质提供了作为γ-富集SPECT（单光子发射计算机断层扫描）配体的额外效用，其可用于表征体内脑CB 1受体结合。
As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure-activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the S-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a gamma-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 receptor binding in vivo.