Vol. 298, Issue 1, 86-102, July 2001

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

Polly J. Baumbarger, Mark Muhlhauser, Jin Zhai, Charles R. Yang and Eric S. Nisenbaum

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana

Positive modulators of glutamate -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 µM) selectively enhanced glutamate-evoked currents through AMPA receptor/channels of acutely isolated pyramidal neurons with considerably greater potency (EC₅₀ = 1.3 ± 0.3 µM) 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 profile by 6- and 3-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, 5 mg/kg, i.v.) receptor antagonists. Collectively, these results demonstrate that 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.