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The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I₂ receptors (I₂-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I₂-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound <b>B06</b> ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, <b>B06</b> revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk <b>B06</b> for progressing in the preclinical development. To further characterize the pharmacological properties of <b>B06</b>, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). <b>B06</b> rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals <b>B06</b> as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I₂-IR as a fresh approach for the therapy of ND.