Escolano Mirón, CarmenAbás Prades, SòniaRodríguez-Arévalo, SergioBagan Polonio, AndreaGriñán Ferré, ChristianVasilopoulou, FoteiniBrocos-Mosquera, IriaMuguruza, CarolinaCallado, Luis F.Pérez, BelénPérez Lozano, PilarBrea, JoséLoza, María IsabelHernández-Hernández, ElenaGarcía-Sevilla, Jesús AGarcía-Fuster, M. JuliaRadan, MilicaDjikic, TeodoraNikolic, KatarinaDíaz, C.Pérez, J.Ramos Guerra, CristianVicente, FilipaMolins i Grau, EliesPallàs i Llibería, Mercè, 1964-2021-07-082021-07-082021-06-220892-6638https://hdl.handle.net/2445/178883I2 receptors (I2-IR) are widely distributed in the central nervous system. I2-IR ligands are associated with a neuroprotective effect but, as I2-IR structure remains unknown, the discovery of better and more selective ligands is necessary to understand the pharmacological and molecular implications of I2-IR. Recently, we described a new imidazoline-structure family which showed high affinity and selectivity for I2-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 I2-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 I2-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 I2-IR ligands, its effectiveness in in vivo models and the possible neuroprotective molecular mechanism mediated by them. This highlights that the modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.application/pdfeng(c) The Federation of American Society of Experimental Biology, 2021Malaltia d'AlzheimerMalalties neurodegenerativesEnvellimentAlzheimer's diseaseNeurodegenerative DiseasesAginginfo:eu-repo/semantics/article7129512021-07-08info:eu-repo/semantics/openAccess