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 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.

Acknowledgements

Over the past 30 years W Froestl has had the pleasure of interacting with many scientists in the GABA community. He apologizes to all colleagues whose work was not discussed here and explicitly acknowledges the valuable contributions made by all scientists working in this fascinating area of neuroscience research.

Financial & competing interests disclosure

The author is an employee of AC Immune SA. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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Funding

The author is an employee of AC Immune SA. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.