piperidines and benzoxazolone

The NMDA receptor plays a key role in the pathogenesis of neurodegenerative disorders including Alzheimer's and Huntington's disease, as well as depression and drug or alcohol dependence. Due to its participation in these pathologies, the development of selective modulators for this ion channel is a promising strategy for rational drug therapy. The prototypical negative allosteric modulator ifenprodil inhibits selectively GluN2B subunit containing NMDA receptors. It was conformationally restricted as 2-methyl-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol, which showed high GluN2B affinity and inhibitory activity. For a better understanding of the relevance of the functional groups and structural elements, the substituents of this 3-benzazepine were removed successively (deconstruction). Then, additional structural elements were introduced (reconstruction) with the aim to analyze, which additional modifications were tolerated by the GluN2B receptor.. The GluN2B affinity was recorded in radioligand receptor binding studies with the radioligand [. The deconstruction approach showed that removal of the methyl moiety and the phenolic OH moiety in 7-positon resulted in almost the same GluN2B affinity as the parent 3-benzazepine. A considerably reduced GluN2B affinity was found for the 3-benzazepine without further substituents. However, removal of one or both OH moieties led to considerably reduced NMDA receptor inhibition. Introduction of a NO. The results reveal an uncoupling of affinity and activity for the tested 3-benzazepines. Strong inhibition of [

Topics: Adrenergic alpha-Antagonists; Allosteric Regulation; Animals; Benzazepines; Benzoxazoles; Binding Sites; Excitatory Amino Acid Antagonists; Humans; Kinetics; Molecular Docking Simulation; Oocytes; Patch-Clamp Techniques; Piperidines; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Radioligand Assay; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Structure-Activity Relationship; Tritium; Xenopus laevis