Novel GABA(B) receptor positive modulators: a patent survey

Positive allosteric modulators of GABA(B) receptors may have a similar potential as positive modulators of GABA(A) receptors, the benzodiazepines discovered in 1957. The discovery of positive allosteric modulators of GABA(B) receptors at Novartis in Basel in 2000 opened the way to search for compounds, which activate GABA(B) receptors without the drawbacks of full agonists, such as desensitization, tolerance, muscle-relaxant effects, hypothermia, and central and gastrointestinal side effects.

Numerous animal experiments point out that several indications can be addressed with positive modulators of GABA(B) receptors, such as depression, anxiety, schizophrenia, neuropathic and chronic pain and treatment of craving for drugs of abuse, such as alcohol, cocaine and nicotine. Peripherally acting compounds may be valuable drugs for the treatment of gastroesophageal reflux disease and irritable bowel syndrome.

An overview on 19 patents in this field, of the different scaffolds for positive modulators of GABA(B) receptors and of the major players in the field.

The search for subtype selective benzodiazepine receptor ligands has proved to be extremely difficult. Positive modulators of GABA(B) receptors may provide novel anxiolytic drugs faster.