Schizophrenia is a mental disorder that causes abnormal thought and behavior, and affects nearly 1% of the population worldwide. The major therapies used to treat schizophrenia are antipsychotics, which block the over-activation of the dopamine receptor system. However, many people with schizophrenia respond poorly to traditional antipsychotics that often are effective in treating the positive symptoms, while not affecting the negative symptoms and cognitive dysfunction, which cause serious adverse effects. Recently, we have designed a potent stereospecific α5-GABAA subtype selective positive allosteric modulator SH-053-2'F-R-CH3 (1), which is nearly silent at the α1, α2, and α3 GABAA/BzR subtypes, and it has been reported to be effective in a MAM-model of schizophrenia. SH-053-2'F-S-CH3 (2) the enantiomer of 1, is an α2-, α3-, and α5-GABAA subtype ligand. Both 1 and 2 exhibit substantial agonist efficacy and high affinity for α5-GABA(A)R with low efficacy at α1. Because of the selective efficacy of 1 at α5 receptors, we have developed a series of analogs which are even more selective at α5 receptors. Reported here are the activity of 1 and 2, and analogs against prepulse inhibition and catalepsy geared towards the treatment of schizophrenia.

Potential novel targets for schizophrenia: Stereospecific GABAA receptor subtype selective imidazobenzodiazepines

251st National Meeting (2016)

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