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 GABA(B) receptor by potentiating GTP gamma S stimulation induced by GABA at 2.5 and 25 mu 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.

Synthesis and pharmacological characterization of 2-(acylamino)thiophene derivatives as metabolically stable, orally effective, positive allosteric modulators of the GABAB receptor

CASTI, ALBERTO;PORCU, ALESSANDRA;CASTELLI, MARIA PAOLA;
2013-01-01

Abstract

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 GABA(B) receptor by potentiating GTP gamma S stimulation induced by GABA at 2.5 and 25 mu 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.
2013
Administration, Oral; Allosteric Regulation; Animals; Baclofen; Chemistry Techniques, Synthetic; Drug Stability; Guanosine 5'-O-(3-Thiotriphosphate); Immobility Response, Tonic; Mice; Microsomes, Liver; NIH 3T3 Cells; Pentobarbital; Rats; Receptors, GABA-B; Thiophenes; Drug Design
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/101446
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