回顾 GABA 能药物的历史。
An historical perspective on GABAergic drugs.
机构信息
AC Immune SA, EPFL PSE B, Lausanne, Switzerland.
出版信息
Future Med Chem. 2011 Feb;3(2):163-75. doi: 10.4155/fmc.10.285.
In 1950, γ-aminobutyric acid (GABA) was discovered in the brain and in 1967 it was recognized as an inhibitory neurotransmitter. The discovery of the benzodiazepines Librium® (launched in 1960) and Valium® by Sternbach initiated huge research activities resulting in 50 marketed drugs. In 1975, Haefely found that GABA is involved in the actions of benzodiazepines. The baclofen-sensitive, bicuculline-insensitive GABA(B) receptor was discovered by Bowery in 1980, and the baclofen-insensitive, bicuculline-insensitive GABA(C) receptor by Johnston in 1984. Barnard & Seeburg reported the cloning of the GABA(A) receptor in 1987, Cutting the GABA(C) receptor in 1991 and Bettler the GABA(B1a) and GABA(B1b) receptors in 1997. Six groups cloned the GABA(B2) receptor in 1998/1999 showing that the GABA(B) receptor functions as a heterodimer with GABA(B1b)/GABA(B2) mediating postsynaptic inhibition and GABA(B1a)/GABA(B2) mediating presynaptic inhibition. Möhler and McKernan dissected the pharmacology of the benzodiazepine-receptor subtypes. Antagonists and positive allosteric modulators of GABA(B) receptors were discovered in 1987 and 2001, respectively. GABA transporter inhibitor, tiagabine, was launched in 1996, a GABA aminotransferase inhibitor, vigabatrin, in 1998 and a glutamic acid decarboxylase activator, pregabalin, in 2004. Most recently, brain-penetrating GABA(C)-receptor antagonists were reported in 2009.
1950 年，γ-氨基丁酸（GABA）在大脑中被发现，1967 年被确认为抑制性神经递质。斯特恩巴赫（Sternbach）发现利眠宁（Librium®，1960 年上市）和安定（Valium®），引发了大量的研究活动，导致 50 种上市药物的诞生。1975 年，哈菲利（Haefely）发现 GABA 参与了苯二氮䓬类药物的作用。鲍厄里（Bowery）于 1980 年发现了巴氯芬敏感、印防己毒素不敏感的 GABA（B）受体，1984 年约翰斯顿（Johnston）发现了巴氯芬不敏感、印防己毒素不敏感的 GABA（C）受体。巴纳德（Barnard）和西伯格（Seeburg）于 1987 年报告了 GABA（A）受体的克隆，1991 年卡廷（Cutting）克隆了 GABA（C）受体，贝特勒（Bettler）于 1997 年克隆了 GABA（B1a）和 GABA（B1b）受体。1998/1999 年，有 6 个研究小组克隆了 GABA（B2）受体，表明 GABA（B）受体作为异二聚体发挥作用，GABA（B1b）/GABA（B2）介导突触后抑制，GABA（B1a）/GABA（B2）介导突触前抑制。莫勒（Möhler）和麦克科南（McKernan）剖析了苯二氮䓬受体亚型的药理学。1987 年和 2001 年分别发现了 GABA（B）受体的拮抗剂和正变构调节剂。GABA 转运体抑制剂噻加宾（tiagabine）于 1996 年上市，GABA 转氨酶抑制剂氨己烯酸（vigabatrin）于 1998 年上市，谷氨酸脱羧酶激活剂普加巴林（pregabalin）于 2004 年上市。最近，2009 年报道了具有脑穿透能力的 GABA（C）受体拮抗剂。
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