Clinical Potential of GABA_B Receptor Modulators

Abstract

Metabotropic gamma-aminobutyric acid(B) (GABAB) 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). GABAB 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, GABAB receptors must exist as a heterodimer consisting of GABAB1 and GABAB2 receptor subtypes with two 7-transmembrane proteins, and these subunits arise from distinct genes. The GABAB1 subunit binds the endogenous ligand within its extracellular N-terminus, whilst the GABAB2 subunit is not only essential for the correct trafficking of the GABAB1 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 GABAB receptor-mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABAB receptor pharmacology and are capable of selectively modifying GABAB receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABAB receptor agonists, and may, therefore, represent a major advance in the drug discovery process.

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…Hence they rather enhance the physiologic pattern of GABA B receptor activation, and so may have less adverse effects than ligands that alter all GABA B receptors. In agreement, allosteric modulators interfere less with locomotor activity (Ong and Kerr, 2005) and do not induce hypothermia (Jacobson and Cryan, 2008).…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…Consistent with these effects, the GABA B receptor agonist baclofen decreases nicotine priming-induced reinstatement of drug seeking [121]. While baclofen also reduces total cigarettes smoked per day and tobacco craving in human smokers [122], compliance is limited by adverse effects including cognitive impairments, sedation, muscle relaxation and tolerance [123]. In contrast, PAMs of GABA B receptors have fewer adverse effects than full agonists.…”

A Submicellar Liquid Chromatographic Method for Quantitative Determination of Muscle Relaxant Drug Baclofen in Solubilized System

“…The most predominant pharmacological effects of baclofen are its muscle relaxant, anti-nociceptive and anti-drug craving properties [9,10] as well as the reduction in cognitive behaviour [11]. Baclofen is used clinically for the treatment of spasticity associated with brain and spinal cord injuries [12], drug addiction and alcoholism [13,14], gastroesophageal reflux disease (GERD) [15], cancer pain [16] and overactive bladder [17][18][19].…”