Novel Imidazoline I 2 Receptor Ligands for Alzheimer's Disease

Imidazoline I 2 receptors (I 2 ‐IRs) are widely distributed in the brain. I 2 ‐IRs are associated with analgesia and human brain disorders, such as depression and Alzheimer's disease (AD). Since, a high density of I 2 ‐IRs proteins is observed in the brain of AD patients these receptors have been suggested as a potential therapeutic target for AD. The I 2 ‐IRs are still orphan proteins from a molecular point of view and the discovery of selective I 2 ‐IRs ligands is likely to enhance both, the AD therapeutic arsenal and serve as valuable tools in defining the pharmacological characterization of I 2 ‐IRs. From the structural point of view, I 2 ‐IRs ligands reported to date feature a 2‐imidazoline substituted nucleus without decoration at any position, indicating that the nature of known IR ligands seems relatively restricted. We have recently reported the pharmacological characterization of a new family of (2‐imidazoline‐4‐yl)phosphonates, prepared by a multicomponent microwaved‐assisted reaction that fulfil the principles of green chemistry. Radioligand binding studies showed that they displayed an outstanding affinity for I 2 ‐IRs and also exhibit neuroprotective properties. This neuroprotection could be associated with the fact that the activation of these receptors leads to decreased calcium levels inhibiting intracellular signals related with molecular pathways implicated in neurodegeneration. In order to further demonstrate neuroprotectant role of new I 2 ‐IRs ligands in senescence and AD, 12 months‐old female senescence accelerated mice prone 8 (SAMP8) were distributed in three groups: Control (n = 10), compound MCR5 (n = 8), and compound MCR9 (n = 8). Treated animals were administered with selected new compounds MCR5 and MCR9 at the dose of 5 mg/kg/day added to drinking water for 4 weeks. The SAMP8 treated group showed increased locomotor activity, less anxiety‐related behavior and decreased cognitive decline based on the results in open field, elevated plus maze, and the novel object recognition test, respectively. A decrease in Tau hiperphosphorylation and sAPPb levels were determined indicating changes in the amyloid processing. The protein levels of the phosphorylated CREB, a transcription factor implicated in the log‐term memory and the neuronal plasticity are found significantly increased, whereas the levels of caspase‐3 and calcineurin decreased. A reduction of the gene expression of some biomarkers of inflammation and oxidative stress was noted. In summary, although the biological effect of I 2 ‐IRs has not been completely defined its interaction with a structurally new family of high affinity selective ligands demonstrated changes on Tau hyperphosphorylation and the amyloid precursor protein (APP) processing, as well as changes related to the oxidative stress, the inflammation and other mechanism that are involved in the pathogenesis of AD. Support or Funding Information SAF2016‐77703‐C2‐1R, Dirección General de Investigación Científica y Técnica. Subdirección General de Proyectos de Investigación.New I 2 receptor ligandsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .