In vitro and in vivo characterization of the novel GABAB receptor positive allosteric modulator, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE)
| Autor: | M. H. Selina Mok, Laura Zonzini, Laurie J. Gordon, Vivian J A Costantini, Massimo Gianotti, Enzo Valerio, Magalie Rocheville, Corrado Carignani, Elisabetta Perdona, Mauro Corsi, Prisca Martinelli, Filippo Visentini, Anna Maria Capelli, Michela Tessari |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Male Baclofen Allosteric modulator Animal food medicine.drug_class Allosteric regulation Drug Evaluation Preclinical CHO Cells Cyclopentanes Pharmacology GABAB receptor Motor Activity Transfection Hippocampus Rats Sprague-Dawley Cellular and Molecular Neuroscience chemistry.chemical_compound Eating Radioligand Assay Cricetinae medicine Animals Humans G protein-coupled inwardly-rectifying potassium channel Molecular Targeted Therapy Receptor gamma-Aminobutyric Acid Cerebral Cortex Neurons Brain Membrane Proteins Electrophysiological Phenomena Rats Pyrimidines nervous system chemistry Receptors GABA-B GABA-B Receptor Agonists Pyrazoles |
| Zdroj: | Neuropharmacology. 61(5-6) |
| ISSN: | 1873-7064 |
| Popis: | There is preclinical evidence supporting the finding that the GABA(B) receptor orthosteric agonist, baclofen, has significant effects on eating behavior suggesting the potential therapeutic application of this compound for the treatment of eating related disorders. However, the wide clinical use of baclofen might be limited by the appearance of sedative and motor impairment effects. The identification of positive allosteric modulators (PAMs) of GABA(B) receptors represents a novel therapeutic approach to reduce the centrally-mediated adverse effects typical of the GABA(B) receptor orthosteric agonist. In the present work, we report the in vitro profile of a novel chemical structure, 2-{1-[2-(4-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-yl]-2-piperidinyl}ethanol (CMPPE) identified by screening the GSK compound collection. CMPPE potentiates GABA-stimulated [(35)S]GTPγS binding to membranes of human recombinant cell line and of rat brain cortex. GABA concentration-response curves (CRC) in the presence of fixed concentrations of CMPPE, in rat native tissue, revealed an increase of both the potency and maximal efficacy of GABA. A similar modulatory effect was observed in GABA(B) receptor-mediated activation of inwardly rectifying potassium channels in hippocampal neurons. CMPPE (30-100 mg/kg) and GS39783 (100 mg/kg) significantly decreased food consumption in rat without impairment on the animal locomotor activity. On the contrary, baclofen (2.5 mg/kg) decreased both food intake and motor performance. All together these findings confirm the role of GABA(B) system in controlling animal food intake and for the first time demonstrate that GABA(B) receptor PAMs may represent a novel pharmacological approach to treat eating disorders without unwanted sedative effects. |
| Databáze: | OpenAIRE |
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