Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I 2 Receptor Ligand B06.
Andrea BagánJose Ángel Morales-GarcíaChristian Griñán-FerréCaridad DiazJosé Pérez Del PalacioMaria C RamosFrancisca VicenteBelén PérezJose BreaMaría Isabel LozaMercé PallàsCarmen EscolanoPublished in: International journal of molecular sciences (2022)
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 I 2 receptors (I 2 -IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I 2 -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 B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06 , we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson's disease (PD). B06 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 B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I 2 -IR as a fresh approach for the therapy of ND.
Keyphrases
- cognitive decline
- cognitive impairment
- drug discovery
- cerebral ischemia
- mild cognitive impairment
- white matter
- anti inflammatory
- single cell
- cell therapy
- endothelial cells
- risk factors
- traumatic brain injury
- signaling pathway
- stem cells
- molecular docking
- subarachnoid hemorrhage
- lipopolysaccharide induced
- brain injury
- multiple sclerosis
- mesenchymal stem cells
- pluripotent stem cells
- functional connectivity
- case control