Allosteric Modulators of GABA(B) Receptors: Mechanism of Action and Therapeutic Perspective

γ-aminobutyric acid (GABA) plays important roles in the central nervous system, acting as a neurotransmitter on both ionotropic ligand-gated Cl(-)-channels, and metabotropic G-protein coupled receptors (GPCRs). These two types of receptors called GABA(A) (and C) and GABA(B) are the targets of major therapeutic drugs such as the anxiolytic benzodiazepines, and antispastic drug baclofen (lioresal®), respectively. Although the multiplicity of GABA(A) receptors offer a number of possibilities to discover new and more selective drugs, the molecular characterization of the GABA(B) receptor revealed a unique, though complex, heterodimeric GPCR. High throughput screening strategies carried out in pharmaceutical industries, helped identifying new compounds positively modulating the activity of the GABA(B) receptor. These molecules, almost devoid of apparent activity when applied alone, greatly enhance both the potency and efficacy of GABA(B) agonists. As such, in contrast to baclofen that constantly activates the receptor everywhere in the brain, these positive allosteric modulators induce a large increase in GABA(B)-mediated responses only WHERE and WHEN physiologically needed. Such compounds are then well adapted to help GABA to activate its GABA(B) receptors, like benzodiazepines favor GABA(A) receptor activation. In this review, the way of action of these molecules will be presented in light of our actual knowledge of the activation mechanism of the GABA(B) receptor. We will then show that, as expected, these molecules have more pronounced in vivo responses and less side effects than pure agonists, offering new potential therapeutic applications for this new class of GABA(B) ligands.