烯胺酮酰胺作为新型口服活性γ-氨基丁酸A型（GABAA）受体调节剂。

Enaminone amides as novel orally active GABAA receptor modulators.

作者信息

Hogenkamp Derk J, Johnstone Timothy B C, Huang Jin-Cheng, Li Wen-Yen, Tran Minhtam, Whittemore Edward R, Bagnera Rudy E, Gee Kelvin W

机构信息

Department of Pharmacology, School of Medicine, Med Surge 2, University of California-Irvine, Irvine, California 92697, USA.

出版信息

J Med Chem. 2007 Jul 12;50(14):3369-79. doi: 10.1021/jm070083v. Epub 2007 Jun 16.

DOI:10.1021/jm070083v

PMID:17571865

Abstract

A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma-aminobutyric acidA (GABAA) receptors. The compounds bind to a novel modulatory site that is independent of the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites. Structure-activity relationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nM based on inhibition of [35S]TBPS binding. The activity of the enaminones as positive allosteric modulators was confirmed with electrophysiological measurements in oocytes expressing alpha1beta2gamma2L GABAA receptors. The i-Pr, s-Bu, c-Pr, and c-Bu amides (16e-h) were orally active in mice with profound central nervous system depressant effects. The i-Pr amide 16e was an orally active anxiolytic in the mouse light-dark paradigm.

摘要

一系列烯胺酮酯和酰胺已被开发为γ-氨基丁酸A（GABAA）受体的强效变构调节剂。这些化合物与一个独立于苯二氮䓬（BZ）、等构GABA和神经活性类固醇结合位点的新型调节位点结合。构效关系（SAR）研究导致合成了体外效力为7 nM的环丁基酰胺16h，其基于对[35S]TBPS结合的抑制作用。通过在表达α1β2γ2L GABAA受体的卵母细胞中的电生理测量，证实了烯胺酮作为正变构调节剂的活性。异丙基、仲丁基、环丙基和环丁基酰胺（16e - h）在小鼠中具有口服活性，并具有显著的中枢神经系统抑制作用。异丙基酰胺16e在小鼠明暗模型中是一种口服活性抗焦虑剂。