Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. Keywords Imidazoline I2 receptors (2-imidazolin-4-yl)phosphonates Behavior Cognition Neurodegeneration Neuroprotection Agin

Monoamine oxidase inhibitory properties of some benzazoles: Structure-; Activity relationships

Benzazoles containing two or three nitrogen atoms were screened for their inhibitory activity toward monoamine oxidases MAO-A and MAO-B. In order to clarify the mechanism of interaction of these compounds with the enzyme, their electronic structure was calculated at the ab initio level and the influence of lipophilicity on activity was investigated. The mode of binding of benzazoles to MAO-B appears different from that of previously investigated heterocycles

Computational comparison of imidazoline association with the 12 binding site in human monoamine oxidases

Imidazoline ligands in I2-type binding sites in the brain alter monoamine turnover and release. One example of an 12 binding site characterized by binding studies, kinetics, and crystal structure has been described in monoamine oxidase B (MAO B). MAO A also binds imidazolines but has a different active site structure. Docking and molecular dynamics were used to explore how 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) binds to MAO A and to explain why tranylcypromine increases tight binding to MAO B. The energy for 2-BFI binding to MAO A was comparable to that for tranylcypromine-modified MAO B, but the location of 2-BFI in the MAO A could be anywhere in the monopartite substrate cavity. Binding to the tranylc-ypromine-modified MAO B was with high affinity and in the entrance cavity as in the crystal structure, but the energies of interaction with the native MAO B were less favorable. Molecular dynamics revealed that the entrance cavity of MAO B after tranylcypromine modification is both smaller and less flexible. This change in the presence of tranylcypromine may be responsible for the greater affinity of tranylcypromine-modified MAO B for imidazoline ligands.</p