Ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate is a novel positive modulator of GABAA receptors.
Ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate (TG41) enhanced the binding both of gamma-aminobutyric acid (GABA) and of flunitrazepam to rat cerebral cortical membranes. Electrophysiological recordings from Xenopus oocytes expressing various recombinant GABA(A) receptor subtypes revealed that TG41 enhanced the function of all receptor subunit combinations tested. The potency of TG41 at receptors containing alpha1, beta2, and gamma2L subunits was greater than that of alphaxalone, etomidate, propofol, or pentobarbital. The potency of TG41 was also greater at receptors containing alpha1 or alpha2 subunits than at those containing alpha4 and it was markedly higher at receptors containing beta2 or beta3 subunits than at those containing beta1. This drug induced a reversible loss of the righting reflex in Xenopus tadpoles and it elicited hypnosis (5 mg/kg) after intravenous administration in rats. These results indicate that the pharmacological profile of TG41 is similar to that of general anesthetics which potentiate the activity of GABA(A) receptors containing the beta2 or beta3 subunit.
Mascia
Maria Paola
MP
Consiglio Nazionale delle Ricerche, Istituto di Neuroscienze, Sezione di Cagliari, Italy. mpmascia@ca.cnr.it
Asproni
Battistina
B
Busonero
Fabio
F
Talani
Giuseppe
G
Maciocco
Elisabetta
E
Pau
Amedeo
A
Cerri
Riccardo
R
Sanna
Enrico
E
Biggio
Giovanni
G
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism; D018757:GABA Modulators / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D011277:Pregnanediones / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018009:Receptors, Glycine / Q000235:genetics / Q000502:physiology; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D014316:Tritium; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D018757:GABA Modulators; D006846:Hydrocarbons, Halogenated; D007093:Imidazoles; D011277:Pregnanediones; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D044406:Receptors, Serotonin, 5-HT3; C503136:ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate; D014316:Tritium; D012701:Serotonin; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C006477:alphaxalone; D010424:Pentobarbital; D003975:Diazepam; D005998:Glycine; D015742:Propofol; D005045:Etomidate