title: 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.
authors.affiliation: AC Immune SA, EPFL PSE B, Lausanne, Switzerland. wolfgang.froestl@acimmune.com
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Froestl
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism; D000075002:Bestrophins; D018118:Chloride Channels / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D018755:GABA Agonists / Q000737:chemistry / Q000378:metabolism; D018756:GABA Antagonists / Q000737:chemistry / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009557:Nipecotic Acids / Q000737:chemistry / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism*
chemical_list: C113133:BEST1 protein, human; D000075002:Bestrophins; D018118:Chloride Channels; D005136:Eye Proteins; D018755:GABA Agonists; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase; D000078308:Tiagabine