An historical perspective on GABAergic drugs

Abstract

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 GABAB receptor was discovered by Bowery in 1980, and the baclofen-insensitive, bicuculline-insensitive GABAC receptor by Johnston in 1984. Barnard & Seeburg reported the cloning of the GABAA receptor in 1987, Cutting the GABAC receptor in 1991 and Bettler the GABAB1a and GABAB1b receptors in 1997. Six groups cloned the GABAB2 receptor in 1998/1999 showing that the GABAB receptor functions as a heterodimer with GABAB1b/GABAB2 mediating postsynaptic inhibition and GABAB1a/GABAB2 mediating presynaptic inhibition. Möhler and McKernan dissected the pharmacology of the benzodiazepine-receptor subtypes. Antagonists and positive allosteric modulators of GABAB 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 GABAC-receptor antagonists were reported in 2009.