Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro

The present study describes the pharmacological activity of two novel posit ive allosteric modulators at AMPA receptors in acutely isolated rat cerebel lar Purkinje neurons and cultured rat hippocampal neurons. Currents elicite d by application of glutamate (100 muM) to isolated cerebellar Purkinje neu rons were potentiated by LY392098, LY404187, cyclothiazide, CX516 and anira cetam. The rank order of potency was LY404187 > LY392098 > cyclothiazide > CX516 > aniracetam. LY392098 displayed a higher maximal efficacy than the o ther compounds examined. AMPA-activated inward currents in cultured rat hip pocampal neurons were potentiated by LY392098, LY404187 and cyclothiazide i n a reversible and concentration-dependent manner although considerable het erogeneity in the magnitude of response from cell to cell was observed. LY3 92098 was ineffective in potentiating AMPA receptor responses when dialyzed via the intracellular solution. The selectivity profiles of the two novel AMPA receptor potentiators were examined. LY392098 or LY404187 had minimal activity on NMDA receptor responses, on voltage-gated calcium channel curre nts in cultured hippocampal neurons and on GluR5 kainate receptor currents in acutely isolated rat dorsal root ganglion neurons. (C) 2001 Elsevier Sci ence Ltd. All rights reserved.