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ABSTRACT: Interest in kainate receptors has increased over the past few years. Our understanding of their physiology and pharmacology has improved markedly since their original cloning and expression in the early 1990s. For example, agonist profiles at recombinant kainate receptors have been used to identify and distinguish kainate receptors in neurons. Furthermore, the development of selective antagonists for kainate receptor subtypes has increased our understanding of the functional roles of kainate receptors in neurons and synaptic transmission. In this review we described the activity of agonists and antagonists at kainate receptors and their selectivity profiles at NMDA and non-NMDA receptors.
Current Pharmaceutical Design 02/2002; 8(10):873-85. · 3.87 Impact Factor
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P Miu,
K R Jarvie,
V Radhakrishnan, M R Gates,
A Ogden,
P L Ornstein,
H Zarrinmayeh,
K Ho,
D Peters,
J Grabell,
A Gupta,
D M Zimmerman,
D Bleakman
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ABSTRACT: The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.
Neuropharmacology 07/2001; 40(8):976-83. · 4.81 Impact Factor
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Journal of Medicinal Chemistry 03/2001; 44(3):302-4. · 5.25 Impact Factor
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ABSTRACT: Pre-pulse inhibition (PPI) of the acoustic startle response is the diminution of the startle response when the startle stimulus is preceded by a weaker, non-startle-eliciting stimulus. Deficits in PPI occur in animals following the administration of apomorphine and in schizophrenic patients. In this study, we examined the ability of the novel atypical antipsychotic olanzapine and the cholecystokinin (CCK)-B antagonist LY288513 to reverse the apomorphine-induced disruption of pre-pulse inhibition. Olanzapine (3.0 and 5.0 mg/kg, i.p.), but not LY288513 (1.0-100 mg/kg, p.o.), blocked apomorphine-induced disruption of PPI. These results indicate that olanzapine, but not LY288513, has dopamine antagonist properties in vivo and predict that olanzapine, but not LY288513, will have antipsychotic activity in man.
Neuroscience Letters 02/1997; 222(1):61-4. · 2.11 Impact Factor
