title: Synthesis and pharmacological evaluation of functionalized isoindolinones on GABA-activated chloride currents in rat cerebellum granule cells in culture.
abstract: A focused N-substituted 3-(2-piperazin-1-yl-2-oxoethyl)-2-(pyridin-2-yl)iso-indolin-1-ones small library was synthesized for modulation of GABA-A receptor function and compared to Zopiclone for the ability to increase GABA-activated chloride currents. All compounds were tested for their effects on GABA-activated chloride currents in rat cerebellar granule cells by use of the whole-cell patch clamp technique. Electrophysiological studies on cultured cerebellar granule cells revealed 3-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-(5-nitropyridin-2-yl)iso-indolin-1-one (Id) as a partial agonist displaying 34% increase of the 10μM GABA evoked peak chloride currents, antagonized by flumazenil. Moreover, a second group of compounds, with bulky functional groups at N-4 position of piperazine, have shown inverse agonist effects. The simple synthetic procedure and the possibility of modulating the efficacy of this class of ligands through additional structural modifications pave the way for further development of new molecules as a novel class of compounds able to interfere with benzodiazepine receptors.
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, SA, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Mola
authors.affiliation: Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, 16146 Genova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gatta
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, SA, Italy; Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Petronzi
authors.affiliation: Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, 16146 Genova, Italy.
authors.forename: Aroldo
authors.initials: A
authors.lastname: Cupello
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, SA, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: De Caprariis
authors.affiliation: Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, 16146 Genova, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Robello
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, SA, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Massa
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, SA, Italy; Department of Experimental Medicine, Second University of Naples, Via Costantinopoli, 16, 80138 Naples, Italy. Electronic address: rosanna.filosa@unina2.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Filosa
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D018118:Chloride Channels / Q000187:drug effects*; D003594:Cytoplasmic Granules / Q000187:drug effects*; D054833:Isoindoles / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D018118:Chloride Channels; D054833:Isoindoles; D005680:gamma-Aminobutyric Acid
keywords: Granule cells; Isoindolinones; Rat cerebellum