GABA allosteric modulators: An overview of recent developments in non-benzodiazepine modulators.

γ-Aminobutyric acid (GABA) is the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the central nervous system (CNS) and also present in the peripheral nervous system, and acts to maintain a balance between excitation and inhibition. GABA acts via three subclasses of receptors termed GABAA, GABAB, and GABAC. GABAA and GABAC receptors are ligand-gated ion channels, while GABAB receptors are G-protein coupled receptors. Each class of GABA receptor has distinct pharmacology and physiology. GABAA receptors are heteropentameric transmembrane protein complexes made up of α1-6, ß1-3, γ1-3, δ, ε, θ, π subunits, giving rise to numerous allosteric binding sites and have thus attracted much attention targets for the treatment of conditions such as epilepsy, anxiety and sleep disorders. The development of ligands for these binding sites has also led to an improved understanding of the different physiological functions and pathological processes and offers the opportunity for the development of novel therapeutics. This review focuses on the medicinal chemistry aspects including drug design, structure-activity relationships (SAR), and mechanism of actions of GABA modulators, including non-benzodiazepine ligands at the benzodiazepine binding site and modulators acting at sites other than the high-affinity benzodiazepine binding site. Recent advances in this area their future applications and potential therapeutic effects are also highlighted.

Sex-differences and stress: effects on regional high and low affinity [3H]GABA binding.

Sex-differences are observed in the GABAergic neurotransmitter system both at rest and following acute stress, yet the brain regions and functional implications of these differences are unknown. We examined sex-differences in the number of low- and high-affinity [3H]GABA binding sites in various brain regions of male and female mice and the effect of stress on such sex-differences. Male (n=6) and female (n=6) QS mice were exposed to a brief swim stress (3 min at 32+/-1 degrees C) either individually or with cage-mates whilst control males (n=6) and females (n=6) remained undisturbed in the home cage. Using quantitative receptor autoradiography, sections of mouse brain were labelled with either 30 or 1000 nM [3H]GABA to label high or low affinity binding sites, respectively. Results indicated that males had more low affinity [3H]GABA binding sites in various forebrain cortical regions but less high affinity binding sites in many of these regions compared with females. Forced swim stress-induced rapid changes in forebrain GABA binding sites in females and group stressed males, suggesting a mechanism for rapid GABAergic adaptations. However the number of functional binding sites for GABA in certain forebrain regions was altered by stress in opposite directions in males and females, such that baseline sex-differences were removed following stress. These results exemplify sex-differences in brain chemical function and stress responses, and are of potential importance for understanding sex-differences in response to GABAergic compounds and disorders with sex and stress as predisposing factors.

Mixed antagonistic effects of bilobalide at rho1 GABAC receptor.

Bilobalide was found to be a moderately potent antagonist with a weak use-dependent effect at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methodology. Antagonism of bilobalide at homomeric rho(1) GABA(C) receptors appeared to be mixed. At low concentration, bilobalide (3 microM) caused a parallel right shift and surmountable GABA maximal response of the GABA dose-response curve characteristic of a competitive antagonist. At high concentrations, bilobalide (10-100 microM) caused nonparallel right shifts and reduced maximal GABA responses of GABA dose-response curves characteristic of a noncompetitive antagonist. The potency of bilobalide appears to be dependent on the concentrations of GABA and was more potent at lower GABA concentrations. The mechanism of action of bilobalide at rho(1) GABA(C) receptors appears to be similar to that of the chloride channel blocker picrotoxinin.

Opposing roles for GABAA and GABAC receptors in short-term memory formation in young chicks.

The inhibitory neurotransmitter GABA has both inhibitory and enhancing effects on short-term memory for a bead discrimination task in the young chick. Low doses of GABA (1-3 pmol/hemisphere) injected into the multimodal association area of the chick forebrain, inhibit strongly reinforced memory, whereas higher doses (30-100 pmol/hemisphere) enhance weakly reinforced memory. The effect of both high and low doses of GABA is clearly on short-term memory in terms of both the time of injection and in the time that the memory loss occurs. We argue on the basis of relative sensitivities to GABA and to selective GABA receptor antagonists that low doses of GABA act at GABAC receptors (EC50 approximately 1 microM) and the higher doses of GABA act via GABAA receptors (EC50 approximately 10 microM). The selective GABAA receptor antagonist bicuculline inhibited strongly reinforced memory in a dose and time dependent manner, whereas the selective GABAC receptor antagonists TPMPA and P4MPA enhanced weakly reinforced in a dose and time dependent manner. Confirmation that different levels of GABA affect different receptor subtypes was demonstrated by the shift in the GABA dose-response curves to the selective antagonists. It is clear that GABA is involved in the control of short-term memory formation and its action, enhancing or inhibiting, depends on the level of GABA released at the time of learning.