cgp-36742 and Cognition-Disorders

SGS-742, a GABA(B) antagonist, is being developed by Saegis, under license from Novartis, for the potential treatment of mild cognitive impairment and Alzheimer's disease (AD). In May 2004, Saegis began enrollment in a phase II trial of SGS-742 in mild-to-moderate AD patients.

Topics: Alzheimer Disease; Animals; Attention Deficit Disorder with Hyperactivity; Clinical Trials as Topic; Cognition Disorders; GABA Antagonists; Humans; Organophosphorus Compounds

The GABA(B) receptor antagonist SGS742 (CGP36742) displays pronounced cognition enhancing effects in mice, young and old rats and in Rhesus monkeys in active and passive avoidance paradigms, in an eight-arm radial maze and a Morris water maze and in a social learning task. SGS742 blocks the late inhibitory postsynaptic potential and the paired-pulse inhibition of population spikes recorded from CA1 pyramidal neurons of the hippocampus of rats in vitro and in vivo. SGS742 significantly enhances the release of glutamate, aspartate, glycine and somatostatin in vivo. Chronic administration of SGS742 causes an up-regulation of GABA(B) receptors in the frontal cortex of rats. Single doses cause a significant enhancement of the mRNA and protein levels of NGF and BDNF in the cortex and hippocampus of rats. The observed antidepressant effects of SGS742 in rats may be explained by these findings. SGS742 was well tolerated in experimental animals as well as in young and elderly human volunteers with an absolute bioavailability in humans of 44%. In a Phase II double-blind, placebo-controlled study in 110 patients with mild cognitive impairment (MCI), oral administration of SGS742 at a dose of 600 mg t.i.d. for 8 weeks significantly improved attention, in particular choice reaction time and visual information processing as well as working memory measured as pattern recognition speed. A second Phase II clinical trial in 280 Alzheimer's disease patients is underway.

Topics: Adult; Aged; Animals; Cognition Disorders; Female; GABA Antagonists; GABA-B Receptor Antagonists; Humans; Male; Mice; Organophosphorus Compounds; Rats