Schizophrenia is a mental disorder which causes the breakdown of thought processes and affects almost 1% of the world's population. The primary treatments prescribed are antipsychotics that focus on suppressing dopamine receptor activity. These antipsychotics can fail to be effective, especially with cognitive dysfunction and the negative symptoms, and can even worsen some of the positive symptoms of schizophrenia. Recently we have developed a chiral subtype selective a5-GABAergic positive allosteric modulator, SH-053-2'F-R-CH3 (1 ), which has very little to no efficacy at the a1, a2, and a3 BzR/GABAergic subtypes. In the MAM model of schizophrenia in rats, 1  reduced the number of spontaneously active dopamine neurons. The enantiomer of 1 , SH-053-2'F-S-CH3 (2 ), is an a2/a3/a5 ligand that has shown to reduce the startle response in the prepulse inhibition model in rats. Because of the low efficacy at a1, there will be a very low abuse potential for these ligands. Both 1  and 2  have shown that they do not cause catalepsy, unlike some antipsychotics prescribed that act as dopamine inverse agonists. These ligands and other related compounds are being developed to treat schizophrenia, especially with regard to the cognitive dysfunction and negative symptoms of schizophrenia.

Chiral subtype selective imidazobenzodiazepines important as potential agents to treat schizophrenia

247th National Meeting (2014)

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