Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06
Bagán, Andrea (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)
Morales-García, José A. (Universidad Complutense de Madrid)
Griñán-Ferré, Christian (Universitat de Barcelona)
Díaz Navarro, Caridad (Fundación MEDINA. Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Del Palacio, José Pérez (Fundación MEDINA. Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Ramos, Maria Carmen (Fundación MEDINA. Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Vicente Pérez, Francisca (Fundación MEDINA. Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Brea, José (University of Santiago de Compostela)
Loza, María Isabel (Universidade de Santiago de Compostela)
Pallàs, Mercè (Universitat de Barcelona)
Escolano, Carmen (Universitat de Barcelona. Departament de Farmacologia, Toxicologia i Química Terapèutica)

Data:	2022
Resum:	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-inflam-matory 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.
Ajuts:	Agencia Estatal de Investigación PID2019-107991RB-I00 Agencia Estatal de Investigación PID2019-106285RB "la Caixa" Foundation 100010434
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Imidazoline I2 receptor ligand ; Pharmacokinetics ; Bicyclic α-iminophosphonate ; Metabolic profile ; Neuroprotection ; Alzheimer's disease ; Parkinson's disease
Publicat a:	International journal of molecular sciences, Vol. 23 Núm. 10 (may 2022) , p. 5408, ISSN 1422-0067

DOI: 10.3390/ijms23105408
PMID: 35628219

21 p, 2.1 MB

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