CNS & Chemistry Expert, AC Immune SA, Lausanne, Switzerland.
Expert Opin Ther Pat. 2010 Aug;20(8):1007-17. doi: 10.1517/13543776.2010.506480.
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.
GABA（B）受体的正变构调节剂可能具有与 1957 年发现的苯二氮䓬类药物类似的潜力，苯二氮䓬类药物是 GABA（A）受体的正变构调节剂。2000 年巴塞尔诺华公司发现 GABA（B）受体的正变构调节剂为寻找化合物开辟了道路，这些化合物可以激活 GABA（B）受体，而没有完全激动剂的缺点，如脱敏、耐受、肌肉松弛作用、体温过低以及中枢和胃肠道副作用。
大量动物实验指出，几种适应症可以用 GABA（B）受体的正变构调节剂来解决，如抑郁症、焦虑症、精神分裂症、神经病理性和慢性疼痛以及治疗滥用药物的渴望，如酒精、可卡因和尼古丁。外周作用化合物可能是治疗胃食管反流病和肠易激综合征的有价值药物。
该领域 19 项专利、不同 GABA（B）受体正变构调节剂支架以及该领域主要参与者的概述。
寻找亚型选择性苯二氮䓬受体配体已被证明极其困难。GABA（B）受体的正变构调节剂可能会更快地提供新型抗焦虑药物。
