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Vol. 60, Issue 5, 963-971, November 2001
-Aminobutyric AcidB Receptors by
2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol
(CGP7930) and its Aldehyde Analog CGP13501
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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
-aminobutyric acidB (GABAB) receptor function. They potentiate GABA-stimulated guanosine
5'-O-(3-[35S]thiotriphosphate)
(GTP[35S]) binding to membranes from a
GABAB(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[35S] binding assay using a native
GABAB receptor preparation (rat brain membranes). Receptor
selectivity is demonstrated because no modulation of glutamate-induced
GTP[35S] 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 GABAB(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 GABAB(1b) receptors. In
addition to GTP[35S] binding, we show that CGP7930
also has modulatory effects in cellular assays such as
GABAB receptor-mediated activation of inwardly rectifying
potassium channels in Xenopus laevis oocytes and
Ca2+ 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
GABAB receptors may represent a novel means of therapeutic
interference with the GABA-ergic system.
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