Positive Modulation of a-Amino-3-hydroxy-5-methyl-4- isoxazole Propionic Acid (AMPA) Receptors in Prefrontal Cortical Pyramidal Neurons by a Novel Allosteric Potentiator

Positive modulators of glutamate a-amino-3-hydroxy-5-meth-yl-4-isoxazole propionic acid (AMPA) receptors can enhance cognitive function in several species. The present experiments compared the actions of a novel biarylpropylsulfonamide com-pound, LY404187, with the prototypical benzoylpiperidine, 1-(quinoxalin-6-ylcarbonyl)-piperidine (CX516), on AMPA re-ceptors of prefrontal cortex (PFC) pyramidal neurons. LY404187 (0.03–10 mM) selectively enhanced glutamate-evoked currents through AMPA receptor/channels of acutely isolated pyramidal neurons with considerably greater potency (EC50 5 1.3 6 0.3 mM) and efficacy (Emax 5 45.3 6 8.0-fold increase) than did CX516 (EC50 5 2.8 6 0.9 mM; Emax 5 4.8 6 1.4-fold increase). Both LY404187 and CX516 increased the potency of the glutamate concentration-response profile by 6