A bicyclic α‑iminophosphonate improves cognitive decline in 5xFAD murine model of neurodegeneration

I 2 receptors (I 2 ‐IR) are widely distributed in the central nervous system. I 2 ‐IR ligands are associated with a neuroprotective effect but, as I 2 ‐IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I 2 ‐IR. Recently, we described a new imidazoline‐structure family which showed high affinity and selectivity for I 2 ‐IR. In vivo studies in mice indicated a neuroprotective role and revealed beneficial effects in behaviour and cognition with a murine model of neurodegeneration, senescence‐accelerated prone mouse (SAMP8). Herein, we report a novel non‐imidazoline‐structure of bicyclic α‐iminophosphonates family with high affinities for I 2 ‐IR. In vivo studies in 5X‐FAD mice (a transgenic representative model of AD) and SAMP8 mice (a model of neurodegeneration linked to aging) showed an improvement in behaviour and cognition, a reduction of AD hallmarks and of neuroinflammation markers for the mice treated with the lead compound B06. After evaluating several pathways associated with neurodegeneration, we demonstrated that CaN pathway plays a critical role on the neuroprotective effects of I 2 ‐IR ligands on SAMP8 mice model. To rule out warnings of the novel family, we calculated DMPK and physicochemical properties for the novel bicyclic α‐iminophosphonates. As well, we carried out drug metabolism, safety studies and in vivo pharmacokinetics for lead compound B06. In summary, we present a novel family of I 2 ‐IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I 2 ‐IR by bicyclic α‐iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.