Two imidazoquinoxaline ligands for the benzodiazepine site sharing a second low affinity site on rat GABA_A receptors but with the opposite functionality

摘要

Imidazoquinoxaline PNU-97775 and imidazoquinoline PNU-101017 are benzodiazepine site ligands with a second low affinity binding site on GABA_A receptors, the occupancy of which at high drug concentrations reverses their positive allosteric activity via the benzodiazepine site, and may potentially minimize abuse liability and physical dependence. In this study we discovered, with two imidazoquinoxaline analogues, that the functionality of the Second site was altered by the nitrogen substituent on the piperazine ring moiety: PNU-100076 with a Hydrogen substituent on the position produced a negative allosteric effect via the second low affinity site, Like the parent compounds, while PNU-100079 with a trifluoroethyl substituent produced a positive Allosteric response.