Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novelallosteric potentiator

Positive modulators of glutamate alpha -amino-3-hydroxy-5-methyl-4-isoxazol e propionic acid (AMPA) receptors can enhance cognitive function in several species. The present experiments compared the actions of a novel biarylpro pylsulfonamide compound, LY404187, with the prototypical benzoylpiperidine, 1-(quinoxalin-6-ylcarbonyl)-piperidine (CX516), on AMPA receptors of prefr ontal cortex (PFC) pyramidal neurons. LY404187 (0.03-10 muM) selectively en hanced glutamate-evoked currents through AMPA receptor/channels of acutely isolated 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 LY404187 and CX516 increased the potency of the glutamate concentration-response pro file by 6- and 8-fold, respectively. Rapid perfusion experiments demonstrat ed that LY404187 produced a marked suppression in the magnitude but no chan ge in the kinetics of receptor desensitization; whereas CX516 produced litt le change in the degree and a modest deceleration of the desensitization pr ocess. In PFC slices, both spontaneous and stimulus-evoked AMPA receptor-me diated excitatory postsynaptic potentials were enhanced by nanomolar concen trations of LY404187. Voltage-sensitive N-methyl-D-aspartate (NMDA) recepto r-dependent synaptic responses also were indirectly augmented as a conseque nce of greater postsynaptic depolarization. Consistent with the in vitro da ta, LY404187 was 1000-fold more potent than CX516 in enhancing the probabil ity of discharge of PFC neurons in response to stimulation of glutamatergic afferents from hippocampus in vivo. This potentiation by LY404187 was redu ced by both selective AMPA (LY300168, 1 mg/kg, i.v.) and NMDA (LY235959, 5 mg/kg, i.v.) receptor antagonists. Collectively, these results demonstrate that LY404187 is an extremely potent and centrally active potentiator of na tive AMPA receptors and has a unique mechanism of action. The therapeutic i mplications of AMPA receptor potentiators are discussed.