Novel GABA_B receptor positive modulators: a patent survey

Abstract

Importance of the field: 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.

Areas covered in this review: 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.

What the reader will gain: 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.

Take home message: 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.

Keywords::

• agonists
• allosteric binding site
• desensitization
• GABA_B receptors
• orthosteric binding site
• positive allosteric modulators

Notes

This box summarizes key points contained in this article.