Synthesis, structure-activity relationships at the GABA(A) receptor in rat brain, and differential electrophysiological profile at the recombinant human GABA(A) receptor of a series of substituted 1,2-diphenylimidazoles

A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate gamma-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA(A) receptors. Many of these compounds enhanced GABA action with potencies...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-04, Vol.48 (7), p.2638-2645
Main Authors: Asproni, Battistina, Talani, Giuseppe, Busonero, Fabio, Pau, Amedeo, Sanna, Sebastiano, Cerri, Riccardo, Mascia, Maria Paola, Sanna, Enrico, Biggio, Giovanni
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Behavior, Animal - drug effects
Brain - drug effects
Brain - metabolism
Female
GABA-A Receptor Agonists
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
In Vitro Techniques
Male
Molecular Sequence Data
Mutagenesis, Site-Directed
Oocytes - drug effects
Oocytes - physiology
Patch-Clamp Techniques
Protein Subunits - genetics
Protein Subunits - physiology
Radioligand Assay
Rats
Rats, Sprague-Dawley
Receptors, GABA-A - genetics
Receptors, GABA-A - physiology
Recombinant Proteins - agonists
Reflex - drug effects
Stereoisomerism
Structure-Activity Relationship
Xenopus laevis
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Summary:A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate gamma-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA(A) receptors. Many of these compounds enhanced GABA action with potencies (EC(50) = 0.19-19 muM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. Structure-activity relationship analysis revealed that the presence of an ester moiety in the imidazole ring was required for full agonist properties, while modifications made in the phenyl rings affected potency and efficacy, with ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate showing the highest potency. These compounds potentiated the [(3)H]GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the beta2 subunit of the GABA(A) receptor into serine reduced the ability of derivative 1i to modulate the GABA function.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049120y