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Titolo:
Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novelallosteric potentiator
Autore:
Baumbarger, PJ; Muhlhauser, M; Zhai, J; Yang, CR; Nisenbaum, ES;
Indirizzi:
Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co Indianapolis IN USA 46285 Labs, Indianapolis, IN 46285 USA
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 1, volume: 298, anno: 2001,
pagine: 86 - 102
SICI:
0022-3565(200107)298:1<86:PMOAP>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
TO-SAMPLE PERFORMANCE; GLUTAMATE RECEPTORS; WORKING-MEMORY; SYNAPTIC TRANSMISSION; NOOTROPIC DRUGS; DESENSITIZATION; CORTEX; HIPPOCAMPAL; ANIRACETAM; CYCLOTHIAZIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Nisenbaum, ES Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Drop 0510, Indianapolis, IN 46285 USA Eli Lilly & Co Drop 0510 Indianapolis IN USA 46285 46285 USA
Citazione:
P.J. Baumbarger et al., "Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novelallosteric potentiator", J PHARM EXP, 298(1), 2001, pp. 86-102

Abstract

Positive modulators of glutamate alpha -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors can enhance cognitive function in several species. The present experiments compared the actions of a novel biarylpropylsulfonamide compound, LY404187, with the prototypical benzoylpiperidine, 1-(quinoxalin-6-ylcarbonyl)-piperidine (CX516), on AMPA receptors of prefrontal cortex (PFC) pyramidal neurons. LY404187 (0.03-10 muM) selectively enhanced glutamate-evoked currents through AMPA receptor/channels of acutelyisolated pyramidal neurons with considerably greater potency (EC50 = 1.3 +/- 0.3 muM) and efficacy (E-max = 45.3 +/- 8.0-fold increase) than did CX516 (EC50 = 2.8 +/- 0.9 mM; E-max = 4.8 +/- 1.4-fold increase). Both LY404187and CX516 increased the potency of the glutamate concentration-response profile by 6- and 8-fold, respectively. Rapid perfusion experiments demonstrated that LY404187 produced a marked suppression in the magnitude but no change in the kinetics of receptor desensitization; whereas CX516 produced little change in the degree and a modest deceleration of the desensitization process. In PFC slices, both spontaneous and stimulus-evoked AMPA receptor-mediated excitatory postsynaptic potentials were enhanced by nanomolar concentrations of LY404187. Voltage-sensitive N-methyl-D-aspartate (NMDA) receptor-dependent synaptic responses also were indirectly augmented as a consequence of greater postsynaptic depolarization. Consistent with the in vitro data, LY404187 was 1000-fold more potent than CX516 in enhancing the probability of discharge of PFC neurons in response to stimulation of glutamatergic afferents from hippocampus in vivo. This potentiation by LY404187 was reduced by both selective AMPA (LY300168, 1 mg/kg, i.v.) and NMDA (LY235959, 5mg/kg, i.v.) receptor antagonists. Collectively, these results demonstratethat LY404187 is an extremely potent and centrally active potentiator of native AMPA receptors and has a unique mechanism of action. The therapeutic implications of AMPA receptor potentiators are discussed.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 11:03:10