GABAB Receptors as Potential Therapeutic Targets

γ-Aminobutyric acid-B (GABAB) receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. To date the only GABAB drug on the market is the agonist baclofen (Lioresal®) that is used to treat severe spasticity of cerebral and spinal origin. In addition baclofen is effective in animal models for many central and peripheral disorders, but sideeffects and the development of tolerance prohibited a more widespread use of this drug in man. Similarly GABAB antagonists show great therapeutic promise but their shortcomings, e.g. the lack of brain penetration or some proconvulsive potential, prevented clinical development. The cloning of GABAB receptors in 1997 revived interest in these receptors as drug targets. The long-awaited availability of the tools that were necessary to develop more selective and safer drugs stimulated an impressive activity in the field. The demonstration that GABAB receptors needed to heteromerize for function provided new insights into the structure of G-protein coupled receptors in general and enabled to identify allosteric GABAB drugs. Gene knockout mice revealed neuronal systems that are under tonic GABAB control and therefore best suited for therapeutic intervention. Significant advances were made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate (GHB), a drug of abuse. Here we provide and update on the molecular composition, the physiology and the pharmacology of GABAB receptors and discuss to what extent our current knowledge influences ongoing and future drug discovery efforts.