title: Hydroxy-1,2,5-oxadiazolyl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and pharmacological characterization of gamma-aminobutyric acid (GABA) related compounds.
abstract: Three 4-substituted 1,2,5-oxadiazol-3-ols containing aminoalkyl substituents (analogues and homologues of gamma-aminobutyric acid (GABA)) were synthesized to investigate the hydroxy-1,2,5-oxadiazolyl moiety as a bioisoster for a carboxyl group at GABA receptors. The pK(a) values of the target compounds were close to those of GABA. At GABA(A) receptors of cultured cerebral cortical neurons, weak agonist and partial agonist profiles were identified, demonstrating the 4-hydroxy-1,2,5-oxadiazol-3-yl unit to be a nonclassical carboxyl group bioisoster.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Marco L
authors.initials: ML
authors.lastname: Lolli
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Hansen
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Petrine
authors.initials: P
authors.lastname: Wellendorph
authors.forename: Karsten
authors.initials: K
authors.lastname: Madsen
authors.forename: Orla Miller
authors.initials: OM
authors.lastname: Larsen
authors.forename: Uffe
authors.initials: U
authors.lastname: Kristiansen
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D010069:Oxadiazoles; D005680:gamma-Aminobutyric Acid