GABAB receptor agonists and antagonists: pharmacological properties and therapeutic possibilities

Abstract

GABA B receptor agonists and antagonists: pharmacological properties and therapeutic possibilities SJ Ennaγ-Aminobutyric acid (GABA), an inhibitory neurotransmitter, is widely distributed throughout the brain and spinal cord. Two major families of GABA receptors have been identified, GABA A and GABAB. While much is known about the pharmacological and molecular properties of GABAA receptors, it is only within the last few years that potent and selective antagonists have been developed for the GABA B site, and only within the past few months that this receptor has been cloned. Thus, tools are now available to define more fully the GABAB receptor in terms of its biology and the therapeutic potential of manipulating this site. Data suggest that, in addition to their established use as muscle relaxants, GABAB receptor agonists possess analgesic and antitussive properties, and may be useful for treating bladder dysfunction. While there is less clinical data on GABA B receptor antagonists, preclinical results indicate that they may be of value in treating absence epilepsy, cognitive dysfunction and, possibly, pulmonary and intestinal disorders. However, for this potential to be fully exploited, it is necessary to identify and characterise molecularly and pharmacologically distinct GABA B receptor subtypes.

The GABAB Receptor—Structure, Ligand Binding and Drug Development

“…The first known GABA derivative was baclofen, which was synthesized in 1962 by adding an halogenated phenyl ring to the β-carbon in an effort to obtain a compound that could penetrate the BBB ( Figure 5) [83,97]. An investigation into baclofen showed that also this compound had multiple limitations; it could not passively penetrate the BBB and had a short half-life requiring frequent administration and thereby causing multiple side effects [83].…”

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…This may support the hypothesis that binge alcohol abuse increases susceptibility to alcohol-induced excitotoxic brain damage to a greater extent than continuous excessive drinking (e.g., Hunt, 1993; see also discussion and references in Bell et al, 2013). Overall, it is likely that glutamatergic neuroadaptations following repeated binge-like drinking behavior lead to a glutamate-GABA functional imbalance (Enna, 1997; Fadda & Rossetti, 1998; Szumlinski et al, 2007), and are responsible, in part, for withdrawal symptomology when ethanol access is terminated. This withdrawal symptomology in turn increases the negative reinforcement-associated properties of continued binge drinking (Everitt & Robbins, 2005; Koob & LeMoal, 2008; Robinson & Berridge, 2008).…”

Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep

“…GABA B receptors are slow-acting metabotropic G-protein-linked dimers containing one GABA B1 (GABA B1a or GABA B1B ) and one GABA B2 subunit [25,28,29] (Figure 2). Fewer drugs have been developed to target the GABA B receptor, baclofen being the most popular agonist, and there are less clinical data available than for the GABA A receptor [27,35]. Although GABA B agonists may promote sleep by increasing the duration of NREM and REM sleep, the effect is believed to be largely off-target [28,36].…”