title: 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).
abstract: 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.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Verona, Italy. Elisabetta.Perdona@aptuit.com
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Perdona'
authors.forename: Vivian J A
authors.initials: VJ
authors.lastname: Costantini
authors.forename: Michela
authors.initials: M
authors.lastname: Tessari
authors.forename: Prisca
authors.initials: P
authors.lastname: Martinelli
authors.forename: Corrado
authors.initials: C
authors.lastname: Carignani
authors.forename: Enzo
authors.initials: E
authors.lastname: Valerio
authors.forename: M H Selina
authors.initials: MH
authors.lastname: Mok
authors.forename: Laura
authors.initials: L
authors.lastname: Zonzini
authors.forename: Filippo
authors.initials: F
authors.lastname: Visentini
authors.forename: Massimo
authors.initials: M
authors.lastname: Gianotti
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.forename: Magalie
authors.initials: M
authors.lastname: Rocheville
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Capelli
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003517:Cyclopentanes / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004435:Eating / Q000187:drug effects / Q000502:physiology; D055724:Electrophysiological Phenomena; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: C569993:2-(1-(2-(4-chlorophenyl)-5-methylpyrazolo(1,5-a)pyrimidin-7-yl)-2-piperidinyl)ethanol; D003517:Cyclopentanes; D058786:GABA-B Receptor Agonists; D008565:Membrane Proteins; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D011720:Pyrazoles; D011743:Pyrimidines; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D001418:Baclofen