title: Selected amino acids, dipeptides and arylalkylamine derivatives do not act as allosteric modulators at GABAB receptors.
abstract: Based on recent reports describing enhancing actions of arylalkylamines (fendiline [N-(3,3-diphenylpropyl)-alpha-methylbenzylamine] and prenylamine [N-(3,3-diphenylpropyl)-alpha-methylphenethylamine]), amino acids (L-phenylalanine, L-leucine and L-isoleucine), and dipeptides (L-Phe-Phe and L-Phe-Leu) on baclofen-induced responses in cortical slices, we have examined whether these compounds might act as positive allosteric modulators at GABA(B) receptors. Unlike the previously described allosteric GABA(B) receptor modulator CGP7930 (2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol), these compounds did not enhance GABA(B) receptor-mediated guanosine 5'-O-(3-thiotriphosphate) [GTP(gamma)35S] binding in native or recombinant cell membrane preparations. Similarly, in a competition binding assay using the antagonist radioligand [3H]CGP62349, CGP7930, but not the other compounds, enhanced the affinities of gamma-aminobutyric acid (GABA) for native GABA(B) receptors from rat brain cortex. Finally, in a cellular assay (Ca(2+) signaling in a recombinant cell line), CGP7930 was again the only compound found to enhance the GABA response. It is concluded that the arylalkylamines, amino acids and dipeptides tested do not act as allosteric modulators at native and recombinant GABA(B) receptors.
authors.affiliation: Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. stephan.urwyler@pharma.novartis.com
authors.forename: Stephan
authors.initials: S
authors.lastname: Urwyler
authors.forename: Tina
authors.initials: T
authors.lastname: Gjoni
authors.forename: Klemens
authors.initials: K
authors.lastname: Kaupmann
authors.forename: Mario F
authors.initials: MF
authors.lastname: Pozza
authors.forename: Johannes
authors.initials: J
authors.lastname: Mosbacher
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology*; D000596:Amino Acids / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058786:GABA-B Receptor Agonists; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid