Modulation of AMPA receptors by a novel organic nitrate

Positive modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) channels reduce desensitization and alter their gating kinetics. We have discovered a novel compound nitric oxide-mimetic that similarly modulates the AMPA receptor by reducing desensitization. This, designated GT-005, belongs to the organic nitrate family that includes the nitrovasodilator nitroglycerine. In acutely isolated hippocampal neurons, GT-005 enhanced kainate (100 μM)-evoked currents with an EC₅₀ of 1.7 ± 0.2 mM and a 176 ± 10% maximal increase in the steady-state current response. Similar results were found in cultured hippocampal neurons (EC₅₀ of 1.3 ± 0.2 mM and a maximal 83 ± 14% increase in the steady-state current response). GT-005 reduced the desensitization of glutamate-evoked currents and slowed the onset of desensitization. This compound also increased the rate of recovery from the desensitized state. With respect to alteration of the excitatory synaptic transmission, GT-005 delayed the decay and increased the frequency of spontaneous miniature excitatory postsynaptic currents (mepsc) recorded in cultured hippocampal neurons.