EDPC: a novel high affinity ligand for the benzodiazepine site on rat GABA(A) receptors.
Rat recombinant alpha1beta2gamma2 gamma-aminobutyric acid type A (GABAA) receptors were functionally expressed in Xenopus laevis oocytes and analyzed for the action of EDPC (Ethyl 3-(1,3-dithian-2-yl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate) using electrophysiological techniques. EDPC inhibited GABA currents at low concentrations (IC50 approximately/= 2 nM). The inhibition by 100 nM EDPC could be reversed by 1 microM of the benzodiazepine antagonistflumazenil (Ro 15-1788), indicating a negative allosteric modulation via the benzodiazepine binding site. In line with this conclusion are radioactive ligand binding studies. EDPC inhibited the binding of 2 nM [3H]flunitrazepam to membranes from the cerebellum or the cortex with IC50 values of about 8 and 25 nM, respectively.
Thomet
U
U
Department of Pharmacology, University of Bern, Switzerland.
Furtmüller
R
R
Sieghart
W
W
Le Hyaric-Almeida
M
M
Rousseau
J F
JF
Dodd
R H
RH
Venault
P
P
Chapouthier
G
G
Sigel
E
E
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D002531:Cerebellum / Q000502:physiology; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009865:Oocytes; D016548:Prosencephalon / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D014982:Xenopus laevis
D018757:GABA Modulators; D008024:Ligands; D011725:Pyridines; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C121709:ethyl 3-(1,3-dithian-2-yl)-1H-pyrrolo(2,3-c)pyridine-5-carboxylate; D005442:Flumazenil