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Title: Synthesis and pharmacological characterization of 2-(acylamino)thiophene derivatives as metabolically stable, orally effective, positive allosteric modulators of the GABAB receptor
Authors: Mugnaini, Claudia 
Pedani, Valentina
Casu, Angelo
Lobina, Carla
Casti, Alberto
Maccioni, Paola
Porcu, Alessandra
Giunta, Daniela
Lamponi, Stefania 
Solinas, Maurizio
Dragoni, Stefania
Valoti, Massimo
Colombo, Giancarlo
Castelli, Maria Paola
Gessa, Gian Luigi
Corelli, Federico 
Issue Date: 2013
Project: None 
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 GTPγS stimulation induced by GABA at 2.5 and 25 μM 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.
ISSN: 1520-4804
DOI: 10.1021/jm400144w
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