Synthesis and Pharmacological Characterization of 2-(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABAB Receptor
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- 作者：Claudia Mugnaini ; Valentina Pedani ; Angelo Casu ; Carla Lobina ; Alberto Casti ; Paola Maccioni ; Alessandra Porcu ; Daniela Giunta ; Stefania Lamponi ; Maurizio Solinas ; Stefania Dragoni ; Massimo Valoti ; Giancarlo Colombo ; Maria Paola Castelli ; Gian Luigi Gessa ; Federico Corelli
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：May 9, 2013
- 年：2013
- 卷：56
- 期：9
- 页码：3620-3635
- 全文大小：559K
- 年卷期：v.56,no.9(May 9, 2013)
- ISSN：1520-4804
文摘
Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABAB receptor by potentiating GTP纬S stimulation induced by GABA at 2.5 and 25 渭M while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177.