5-hydroxytryptamine2A receptor inverse agonists as antipsychotics.
5-hydroxytryptamine2A receptor inverse agonists as antipsychotics.
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发表时间：
2001-10
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通讯作者：
D. Weiner;E. Burstein;N. Nash;G. Croston;E. Currier;K. Vanover;S. C. Harvey;E. Donohue;H. Hansen;M. AnderssonCarl;T. Spalding;D. Gibson;K. Krebs-Thomson;S. Powell;M. Geyer;U. Hacksell;M. Brann
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作者：
D. Weiner;E. Burstein;N. Nash;G. Croston;E. Currier;K. Vanover;S. C. Harvey;E. Donohue;H. Hansen;M. AnderssonCarl;T. Spalding;D. Gibson;K. Krebs-Thomson;S. Powell;M. Geyer;U. Hacksell;M. Brann
我们已经使用了基于细胞的功能测定，以确定广泛的中枢神经系统活性化合物的药理学概况作为激动剂，竞争性拮抗剂，并在几乎所有已知的单胺能G蛋白偶联受体（GPCR）亚型的反向激动剂。40种抗精神病药物的详细分析证实，正如预期的那样，这些药物中的大多数是多巴胺D2受体的强效竞争性拮抗剂。令人惊讶的是，该分析还揭示了大多数是有效的和完全有效的5-羟色胺（5-HT）2A受体反向激动剂。这类化合物没有其他的分子性质是普遍共有的。此外，受体效力的比较显示，具有最高锥体外系副作用（EPS）倾向的抗精神病药物对D2受体的效力显著更强，保留EPS的非典型药物对5-HT 2A受体的效力相对更高，而三种药物对5-HT 2A受体的效力显著更强。功能性高通量筛选不同的化学库确定了530个配体与反向激动剂活性的5-HT 2A受体，包括几个系列的化合物相关的已知抗精神病药物，以及一些新的化学。一种新的化学系列之一的类似物AC-90179，对剩余的单胺能GPCR进行了反向分析，发现是一种高度选择性的5-HT 2A受体反向激动剂。AC-90179的行为药理学具有非典型抗精神病药物的特征。
We have used a cell-based functional assay to define the pharmacological profiles of a wide range of central nervous system active compounds as agonists, competitive antagonists, and inverse agonists at almost all known monoaminergic G-protein-coupled receptor (GPCR) subtypes. Detailed profiling of 40 antipsychotics confirmed that as expected, most of these agents are potent competitive antagonists of the dopamine D2 receptor. Surprisingly, this analysis also revealed that most are potent and fully efficacious 5-hydroxytryptamine (5-HT)2A receptor inverse agonists. No other molecular property was shared as universally by this class of compounds. Furthermore, comparisons of receptor potencies revealed that antipsychotics with the highest extrapyramidal side effects (EPS) liability are significantly more potent at D2 receptors, the EPS-sparing atypical agents had relatively higher potencies at 5-HT2A receptors, while three were significantly more potent at 5-HT2A receptors. Functional high-throughput screening of a diverse chemical library identified 530 ligands with inverse agonist activity at 5-HT2A receptors, including several series of compounds related to known antipsychotics, as well as a number of novel chemistries. An analog of one of the novel chemical series, AC-90179, was pharmacologically profiled against the remaining monoaminergic GPCRs and found to be a highly selective 5-HT2A receptor inverse agonist. The behavioral pharmacology of AC-90179 is characteristic of an atypical antipsychotic agent.