Novel compounds selectively enhance delta subunit containing GABA sub(A) receptors and increase tonic currents in thalamus

• Published in: Neuropharmacology 2009-01, Vol.56 (1), p.182-189
• Main Authors: Wafford, KA, Van Niel, MB, Ma, Q P, Horridge, E, Herd, M B, Peden, DR, Belelli, D, Lambert, J J
• Format: Article
• Language: English
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2008.08.004

Inhibition in the brain is dominated by the neurotransmitter gamma - aminobutyric acid (GABA); operating through GABA sub(A) receptors. This form of neural inhibition was presumed to be mediated by synaptic receptors, however recent evidence has highlighted a previously unappreciated role for extrasynaptic GABA sub(A) receptors in controlling neuronal activity. Synaptic and extrasynaptic GABA sub(A) receptors exhibit distinct pharmacological and biophysical properties that differentially influence brain physiology and behavior. Here we used a fluorescence-based assay and cell lines expressing recombinant GABA sub(A) receptors to identify a novel series of benzamide compounds that selectively enhance, or activate alpha 4 beta 3 delta GABA sub(A) receptors (cf. alpha 4 beta 3 gamma 2 and alpha 1 beta 3 gamma 2). Utilising electrophysiological methods, we illustrate that one of these compounds, 4-chloro-N-[6,8-dibromo-2-(2- thienyl)imidazo[1,2-a]pyridine-3-yl benzamide (DS1) potently (low nM) enhances GABA-evoked currents mediated by alpha 4 beta 3 delta receptors. At similar concentrations DS1 directly activates this receptor and is the most potent known agonist of alpha 4 beta 3 delta receptors. 4-chloro-N-[2-(2- thienyl)imidazo[1,2-a]pyridine-3-yl benzamide (DS2) selectively potentiated GABA responses mediated by alpha 4 beta 3 delta receptors, but was not an agonist. Recent studies have revealed a tonic form of inhibition in thalamus mediated by the alpha 4 beta 2 delta extrasynaptic GABA sub(A) receptors that may contribute to the regulation of thalamocortical rhythmic activity associated with sleep, wakefulness, vigilance and seizure disorders. In mouse thalamic relay cells DS2 enhanced the tonic current mediated by alpha 4 beta 2 delta receptors with no effect on their synaptic GABA sub(A) receptors. Similarly, in mouse cerebellar granule cells DS2 potentiated the tonic current mediated by alpha 6 beta delta receptors. DS2 is the first selective positive allosteric modulator of delta -GABA sub(A) receptors and such compounds potentially offer novel therapeutic opportunities as analgesics and in the treatment of sleep disorders. Furthermore, these drugs may be valuable in elucidating the physiological and pathophysiological roles played by these extrasynaptic GABA sub(A) receptors.