Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

Int J Mol Sci. 2022 May 12;23(10):5408. doi: 10.3390/ijms23105408.

Abstract

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 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 I2-IR as a fresh approach for the therapy of ND.

Keywords: Alzheimer’s disease; Parkinson’s disease; bicyclic α-iminophosphonate; imidazoline I2 receptor ligand; metabolic profile; neuroprotection; pharmacokinetics.

MeSH terms

  • Animals
  • Brain / metabolism
  • Humans
  • Imidazolines*
  • Ligands
  • Mice
  • Oxidopamine / pharmacology
  • Parkinson Disease* / metabolism

Substances

  • Imidazolines
  • Ligands
  • Oxidopamine

Grants and funding

This research was funded by the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2019-106285RB). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2020 research and innovation programme. Financial support was provided for A.B. (Institute of Biomedicine UB_2018). A.B., C.G.-F., M.P., and C.E., belonging to 2017SGR106 (Generalitat de Catalunya). MEDINA authors disclosed the receipt of financial support from Fundación MEDINA, a public–private partnership of Merck Sharp and Dohme de España S.A./Universidad de Granada/Junta de Andalucía (PIN-0474-2016). J.B. and M.I.L. gratefully acknowledge support from Xunta de Galicia (ED431C 2018/21 and ED431G 2019/02) and the European Regional Development Fund (ERDF).