1 research outputs found
Synthesis and Pharmacological Characterization of 2‑(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABA<sub>B</sub> Receptor
Two
recently reported hit compounds, COR627 and COR628, underpinned the
development of a series of 2-(acylamino)Âthiophene derivatives. Some
of these compounds displayed significant activity in vitro as positive
allosteric modulators of the GABA<sub>B</sub> 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 <b>6</b>, <b>10</b>, and <b>11</b> 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