CGP 7930

Differential modulation by the GABAB receptor allosteric potentiator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930) of synaptic transmission in the rat hippocampal CA1 area.[Pubmed:16507713]

J Pharmacol Exp Ther. 2006 Jun;317(3):1170-7.

The recently discovered GABAB receptor-positive allosteric modulators enhanced the potency and efficacy of GABAB receptor agonists in in vitro experiments. These GABAB modulators also attenuated reward and anxiety in behavioral experiments without causing the untoward side effects associated with GABAB receptor activation by agonist administration and hence exhibited potential therapeutic utility. However, the underlying molecular mechanisms enabling the GABAB allosteric modulators to dissociate from the GABAB agonistic side effects remain elusive. To address this question, we have examined the effects of a typical GABAB modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930), on GABAB receptor-mediated modulations of both the excitatory and the delayed inhibitory components of hippocampal CA1 synaptic transmission. Using baclofen as an agonist and a multielectrode recording system, we recorded GABAB receptor-mediated modulations of both the field excitatory postsynaptic potentials and the population spikes simultaneously, as well as the paired-pulse inhibition of the population spike. We found that CGP7930 selectively enhanced the baclofen-induced modulation of synaptic inhibition without having any significant effects on the synaptic excitation. Our experiments have therefore revealed a pathway-selective differential modulation of synaptic transmission by CGP7930. This finding provides a synaptic mechanism to support the hypothesis that GABAB potentiators may be a better therapeutic alternative than GABAB agonists for central nervous system disorders.

The GABA(B) receptor allosteric modulator CGP7930, like baclofen, reduces operant self-administration of ethanol in alcohol-preferring rats.[Pubmed:16406445]

Neuropharmacology. 2006 Apr;50(5):632-9.

GABA systems have been implicated as targets for ethanol at the cellular, molecular and behavioural level. The present study was designed to further examine the potential of the GABA(B) receptor as a target for regulating operant alcohol responding. Given that the prototypic agonist, baclofen, reduces the self-administration of alcohol, we hypothesized that the GABA(B) receptor allosteric modulator, CGP7930, might have similar actions but a reduced side-effect profile. In this context, inbred alcohol-preferring (iP) rats were trained to respond for 10% v/v ethanol in a fixed ratio paradigm; all drug testing was performed under an FR3 schedule. Both baclofen and CGP7930 independently reduced voluntary responding for 10% ethanol in a dose-related manner. Neither drug impacted upon responding for water. A combination of subthreshold doses of baclofen and CGP7930 was also able to reduce operant responding for ethanol, suggesting that CGP7930 is indeed acting to facilitate GABA(B) receptor-mediated signalling in this paradigm. These data demonstrate the potential of positive allosteric modulators of metabotropic GABA(B) receptors to regulate alcohol responding.

Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501.[Pubmed:11641424]

Mol Pharmacol. 2001 Nov;60(5):963-71.

The compounds CGP7930 [2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] and its close analog CGP13501 were identified as positive modulators of gamma-aminobutyric acid(B) (GABA(B)) receptor function. They potentiate GABA-stimulated guanosine 5'-O-(3-[(35)S]thiotriphosphate) (GTP gamma[(35)S]) binding to membranes from a GABA(B(1b/2)) expressing Chinese hamster ovary (CHO) cell line at low micromolar concentrations and are ineffective in the absence of GABA. The structurally related compounds propofol and malonoben are inactive. Similar effects of CGP7930 are seen in a GTP gamma[(35)S] binding assay using a native GABA(B) receptor preparation (rat brain membranes). Receptor selectivity is demonstrated because no modulation of glutamate-induced GTP gamma[(35)S] binding is seen in a CHO cell line expressing the metabotropic glutamate receptor subtype 2. Dose-response curves with GABA in the presence of different fixed concentrations of CGP7930 reveal an increase of both the potency and maximal efficacy of GABA at the GABA(B(1b/2)) heteromer. Radioligand binding studies show that CGP7930 increases the affinity of agonists but acts at a site different from the agonist binding site. Agonist affinity is not modulated by CGP7930 at homomeric GABA(B(1b)) receptors. In addition to GTP gamma[(35)S] binding, we show that CGP7930 also has modulatory effects in cellular assays such as GABA(B) receptor-mediated activation of inwardly rectifying potassium channels in Xenopus laevis oocytes and Ca(2+) signaling in human embryonic kidney 293 cells. Furthermore, we show that CGP7930 enhances the inhibitory effect of L-baclofen on the oscillatory activity of cultured cortical neurons. This first demonstration of positive allosteric modulation at GABA(B) receptors may represent a novel means of therapeutic interference with the GABA-ergic system.