GYKI 47261 dihydrochloride

GYKI 47261 dihydrochloride is a selective and non-competitive antagonist of AMPA receptor with IC50 value of 2.5 μM [1].

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) is an ionotropic transmembrane receptor for glutamate and mediates fast synaptic transmission in the central nervous system. AMPA receptors are oligomeric assemblies of four protein subunits, GluR1-4.

GYKI 47261 dihydrochloride is a selective and non-competitive AMPA receptor antagonist. In isolated cerebellar Purkinje cells, GYKI 47261 (10 μM) inhibited currents induced by kainate or AMPA in a non-competitive way [1]. In rat hepatocytes, GYKI-47261 (10 μM) significantly increased CYP2E1 activity. In human hepatocytes, GYKI-47261 produced the maximal induction at 0.01 μM [2].

In mice, GYKI 47261 induced muscle relaxant effects with ED50 values of 15.8-36.5 mg/kg. In a transient focal ischemia rat model, GYKI 47261 significantly reduced infarct size by 62.3-67.4%. In mice, GYKI 47261 effectively reduced oxotremorine-induced tremor and inhibited MPTP-induced neurotoxicity [1]. In Parkinson’s disease rat model, administration of GYKI-47261 and MK-801 completely normalized the response shortening induced by levodopa. In monkeys, administration of amantadine and GYKI-47261 significantly reduced dyskinesias induced by levodopa by 51% [3].

References:
[1].  Abrahám G, Sólyom S, Csuzdi E, et al. New non competitive AMPA antagonists. Bioorg Med Chem, 2000, 8(8): 2127-2143.
[2].  Tamási V, Hazai E, Porsmyr-Palmertz M, et al. GYKI-47261, a new AMPA [2-amino-3-(3-hydroxymethylisoxazole-4-yl)propionic acid] antagonist, is a CYP2E1 inducer. Drug Metab Dispos, 2003, 31(11): 1310-1314.
[3].  Bibbiani F, Oh JD, Kielaite A, et al. Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD. Exp Neurol, 2005, 196(2): 422-429.

Combined blockade of AMPA and NMDA glutamate receptors reduces levodopa-induced motor complications in animal models of PD.[Pubmed:16203001]

Exp Neurol. 2005 Dec;196(2):422-9.

AMPA and NMDA receptors, abundantly expressed on striatal medium spiny neurons, have been implicated in the regulation of corticostriatal synaptic efficacy. To evaluate the contribution of both glutamate receptor types to the pathogenesis of motor response alterations associated with dopaminergic treatment, we studied the ability of the selective AMPA receptor antagonist GYKI-47261 and the selective NMDA receptor antagonists, MK-801 and amantadine, to mitigate these syndromes in rodent and primate models of Parkinson's disease. The effects of GYKI-47261 and amantadine (or MK-801), alone and in combination, were compared for their ability to modify dyskinesias induced by levodopa. In rats, simultaneous administration of subthreshold doses of AMPA and NMDA receptor antagonists completely normalized the wearing-off response to acute levodopa challenge produced by chronic levodopa treatment (P < 0.05). In primates, the glutamate antagonists GYKI-47261 and amantadine, co-administered at low doses (failing to alter dyskinesia scores), reduced levodopa-induced dyskinesias by 51% (P < 0.05). The simultaneous AMPA and NMDA receptor blockade acts to provide a substantially greater reduction in the response alterations induced by levodopa than inhibition of either of these receptors alone. The results suggest that mechanisms mediated by both ionotropic glutamate receptors make an independent contribution to the pathogenesis of these motor response changes and further that a combination of both drug types may provide relief from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone.

New non competitive AMPA antagonists.[Pubmed:11003158]

Bioorg Med Chem. 2000 Aug;8(8):2127-43.

New halogen atom substituted 2,3-benzodiazepine derivatives condensed with an azole ring on the seven membered part of the ring system of type 3 and 4 as well as 5 and 6 were synthesized. It was found that chloro-, dichloro- and bromo-substitutions in the benzene ring and additionally imidazole ring condensation on the diazepine ring can successfully substitute the methylenedioxy group in the well known molecules GYKI 52466 (1) and GYKI 53773 (2) and the 3-acetyl-4-methyl structural feature in 2, respectively, preserving the highly active AMPA antagonist characteristic of the original molecules. From the most active compounds (3b,i) 3b (GYKI 47261) was chosen for detailed investigations. 3b revealed an excellent, broad spectrum anticonvulsant activity against seizures evoked by electroshock and different chemoconvulsive agents indicating a possible antiepileptic efficacy. 3b was found to be highly active in a transient model of focal ischemia predictive of a therapeutic value in human stroke. 3b also reversed the dopamine depleting effect of MPTP and antagonized the oxotremorine induced tremor in mice indicating a potential antiparkinson activity.