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Research ArticleArticle

Positive Allosteric Modulation of Native and Recombinant γ-Aminobutyric AcidB Receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its Aldehyde Analog CGP13501

Stephan Urwyler, Johannes Mosbacher, Kurt Lingenhoehl, Jakob Heid, Karin Hofstetter, Wolfgang Froestl, Bernhard Bettler and Klemens Kaupmann
Molecular Pharmacology November 2001, 60 (5) 963-971; DOI: https://doi.org/10.1124/mol.60.5.963
Stephan Urwyler
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Johannes Mosbacher
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Kurt Lingenhoehl
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Jakob Heid
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Karin Hofstetter
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Wolfgang Froestl
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Bernhard Bettler
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Klemens Kaupmann
Novartis Pharma AG, TA Nervous System, Basel, Switzerland
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Abstract

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 γ-aminobutyric acidB (GABAB) receptor function. They potentiate GABA-stimulated guanosine 5′-O-(3-[35S]thiotriphosphate) (GTPγ[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 GTPγ[35S] binding assay using a native GABAB receptor preparation (rat brain membranes). Receptor selectivity is demonstrated because no modulation of glutamate-induced GTPγ[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 GTPγ[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 ofl-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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Molecular Pharmacology: 60 (5)
Molecular Pharmacology
Vol. 60, Issue 5
1 Nov 2001
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Positive Allosteric Modulation of Native and Recombinant γ-Aminobutyric AcidB Receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its Aldehyde Analog CGP13501
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Research ArticleArticle

Positive Allosteric Modulation of Native and Recombinant γ-Aminobutyric AcidB Receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its Aldehyde Analog CGP13501

Stephan Urwyler, Johannes Mosbacher, Kurt Lingenhoehl, Jakob Heid, Karin Hofstetter, Wolfgang Froestl, Bernhard Bettler and Klemens Kaupmann
Molecular Pharmacology November 1, 2001, 60 (5) 963-971; DOI: https://doi.org/10.1124/mol.60.5.963

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Research ArticleArticle

Positive Allosteric Modulation of Native and Recombinant γ-Aminobutyric AcidB Receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its Aldehyde Analog CGP13501

Stephan Urwyler, Johannes Mosbacher, Kurt Lingenhoehl, Jakob Heid, Karin Hofstetter, Wolfgang Froestl, Bernhard Bettler and Klemens Kaupmann
Molecular Pharmacology November 1, 2001, 60 (5) 963-971; DOI: https://doi.org/10.1124/mol.60.5.963
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