Received for publication April 14, 2003.
Revised May 15, 2003.
Accepted for publication June 11, 2003.

GS39783 (N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro- pyrimidine-4,6-diamine) and Structurally Related Compounds: Novel Allosteric Enhancers of - Aminobutyric Acid_B Receptor Function

Abstract

GS39783 (N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro- pyrimidine-4,6-diamine) and structurally related compounds are described as novel allosteric enhancers of GABA_B receptor function. They potentiate GABA- stimulated GTP()³⁵S binding to membranes from a GABA_B(1b/2) expressing CHO cell line at low micromolar concentrations, but do not stimulate GTP()³⁵S binding by themselves. Similar effects of GS39783 are seen on native GABA_B receptors in rat brain membranes. Dose-response curves with GABA in the presence of different fixed concentrations of GS39783 reveal an increase of both the potency and maximal efficacy of GABA at the GABA_B(1b/2) heterodimer. In radioligand binding experiments, GS39783 reduces the kinetic rate constants of the association and dissociation of [³H]APPA, resulting in a net increase in affinity for the agonist radioligand. In equilibrium binding experiments (displacement of the antagonist ligand [³H]CGP62349), GS39783 increases agonist affinities. Agonist displacement curves are biphasic, probably reflecting the G-protein - coupled and uncoupled states of the receptor. The proportion of the high affinity component is increased by GS39783, suggesting that the G protein - coupling of the receptor is also promoted by the positive modulator. We also show that GS39783 has modulatory effects in cellular assays such as GABA_B receptor mediated activation of inwardly rectifying potassium channels in Xenopus oocytes and Ca²⁺ signaling in HEK293 cells. In a more physiological context, GS39783 is shown to suppress paired pulse inhibition in rat hippocampal slices. This effect is reversed by the competitive GABA_B receptor antagonist CGP55845A and is produced most likely by enhancing the effect of synaptically released GABA at presynaptic GABA_B receptors.

Key words: GABA, GABA B receptor, GS39783, allosteric modulators, cellular assays, paired pulse inhibition

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