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.
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.
Lolli
Marco L
ML
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
Hansen
Suzanne L
SL
Rolando
Barbara
B
Nielsen
Birgitte
B
Wellendorph
Petrine
P
Madsen
Karsten
K
Larsen
Orla Miller
OM
Kristiansen
Uffe
U
Fruttero
Roberta
R
Gasco
Alberto
A
Johansen
Tommy N
TN
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
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