Clinical Potential of GABA B Receptor Modulators

Metabotropic γ‐aminobutyric acid B (GABA B ) receptors for the major inhibitory transmitter GABA, together with metabotropic glutamate (mGLuRs) receptors, the extracellular calcium‐sensing receptors (CaSRs), some V2R pheromone receptors and T1R taste receptors, belong to the family of 3 G‐protein‐coupled receptors (GPCRs). GABA B receptors are known to control neuronal excitability and modulate synaptic neurotransmission, playing a very important role in many physiological activities. These receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, depression, schizophrenia and drug addiction. To form a functional receptor entity, GABA B receptors must exist as a heterodimer consisting of GABA B1 and GABA B2 receptor subtypes with two 7‐transmembrane proteins, and these subunits arise from distinct genes. The GABA B1 subunit binds the endogenous ligand within its extracellular N‐terminus, whilst the GABA B2 subunit is not only essential for the correct trafficking of the GABA B1 subunit to the cell surface, but is also responsible for the interaction of the receptor with its cognate G‐protein. Allosteric modulation has recently been recognized as an alternative pharmacological approach to gain selectivity in drug action. It is now generally accepted that modulators acting at the allosteric sites provide a novel perspective for the development of subtype‐selective agents acting at GPCRs. These agents interact with allosteric binding sites quite separate from the highly conserved agonist binding region. In this review, we present a new class of phenylalkylamines, based on the lead compound fendiline, that are potent positive potentiators of GABA B receptor‐mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABA B receptor pharmacology and are capable of selectively modifying GABA B receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABA B receptor agonists, and may, therefore, represent a major advance in the drug discovery process.