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

K. A. Wafford (Lead / Corresponding author), M. B. van Niel, Q. P. Ma, E. Horridge, M.B. Herd, D.R. Peden, D. Belelli, Jeremy Lambert

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    110 Citations (Scopus)

    Abstract

    Inhibition in the brain is dominated by the neurotransmitter gamma-aminobutyric acid (GABA); operating through GABA(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(A) receptors in controlling neuronal activity. Synaptic and extrasynaptic GABA(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(A) receptors to identify a novel series of benzamide compounds that selectively enhance, or activate alpha 4 beta 3 delta GABA(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(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(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(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(A) receptors. (C) 2008 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)182-189
    Number of pages8
    JournalNeuropharmacology
    Volume56
    Issue number1
    DOIs
    Publication statusPublished - Jan 2009

    Keywords

    • GABA(A) receptor
    • Delta subunit
    • Allosteric modulator
    • Thalamus
    • Extrasynaptic
    • KNOCKOUT MICE
    • PHARMACOLOGICAL CHARACTERIZATION
    • NEUROSTEROID MODULATION
    • DENTATE GYRUS
    • OVARIAN CYCLE
    • RELAY NEURONS
    • INHIBITION
    • EXPRESSION
    • SLEEP
    • SUSCEPTIBILITY

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