Bicyclic α-Iminophosphonates as High Affinity Imidazoline I₂ Receptor Ligands for Alzheimer’s Disease

Abstract

Imidazoline I 2 receptors (I 2-IR), widely distributed in the CNS and altered in patients that suffered from neurodegenerative disorders, are orphan from the structural point of view and new I 2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and 3D-QSAR studies of a new family of bicyclic -iminophosphonates endowed with relevant affinities for human brain I 2-IR. Acute treatment in mice with a selected compound significantly decreased the FADD protein in the hippocampus, a key marker in neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore bicyclic -iminophosphonates are tools that may open new therapeutic avenues for I 2-IR, particularly for unmet neurodegenerative conditions.

Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer's disease

“…However, they did not investigate markers of neurodegeneration, glial activation or amyloid pathology, aside from some reductions in the levels of soluble APP-β fragment (Abás et al, 2020). Interestingly, the effects of BU224 treatment on reversing cognitive deficits observed in our study were not mediated by changes in amyloid deposition in the AD mouse model or in vitro.…”

“…Another recent study exploring the effect of chronic treatment with a new family of bicyclic α‐iminophosphonates with affinity for I 2 receptors reported improvements in memory deficits in 5XFAD mice using the novel object recognition test (Abás et al, 2020). However, they did not investigate markers of neurodegeneration, glial activation or amyloid pathology, aside from some reductions in the levels of soluble APP‐β fragment (Abás et al, 2020). Interestingly, the effects of BU224 treatment on reversing cognitive deficits observed in our study were not mediated by changes in amyloid deposition in the AD mouse model or in vitro .…”

“…Another recent study exploring the effect of chronic treatment with a new family of bicyclic α-iminophosphonates with affinity for I 2 receptors reported improvements in memory deficits in 5XFAD mice using the novel object recognition test (Abás et al, 2020).…”

Disease‐modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: a comparative study with donepezil

“…Most notably, the density of I 2 receptors was found to increase in AD patients (Garcia-Sevilla et al, 1998). Several lines of evidence provided by our group demonstrated that selective I 2 ligands protected against cognitive impairment and ameliorated AD pathological features related to amyloid precursor protein processing, tau hyperphosphorylation, neuroinflammation and oxidative stress processes, using well-established AD animal models (Ab as et al, 2017(Ab as et al, , 2020Griñ an-Ferré et al, 2019;.…”

“…Most notably, the density of I 2 receptors was found to increase in AD patients (Garcia‐Sevilla et al, 1998). Several lines of evidence provided by our group demonstrated that selective I 2 ligands protected against cognitive impairment and ameliorated AD pathological features related to amyloid precursor protein processing, tau hyperphosphorylation, neuroinflammation and oxidative stress processes, using well‐established AD animal models (Abás et al, 2017, 2020; Griñán‐Ferré et al, 2019; Vasilopoulou, Griñán‐Ferré, et al, 2020). Likewise, agmatine, the proposed endogenous ligand for I 2 receptors, prevented cognitive deficits in amyloid‐β 1–42 peptide‐injected mice and of note, its effect was augmented and attenuated by I 2 agonists and antagonists, respectively (Kotagale et al, 2020).…”