Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06
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<sub>2</sub> receptors (I<sub>2</sub>-IR) that are widely distributed in the br...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/10/5408 |
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| author | Andrea Bagán José A. Morales-García Christian Griñán-Ferré Caridad Díaz José Pérez del Palacio Maria C. Ramos Francisca Vicente Belén Pérez José Brea María Isabel Loza Mercè Pallàs Carmen Escolano |
| author_facet | Andrea Bagán José A. Morales-García Christian Griñán-Ferré Caridad Díaz José Pérez del Palacio Maria C. Ramos Francisca Vicente Belén Pérez José Brea María Isabel Loza Mercè Pallàs Carmen Escolano |
| author_sort | Andrea Bagán |
| collection | DOAJ |
| description | 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<sub>2</sub> receptors (I<sub>2</sub>-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I<sub>2</sub>-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 I<sub>2</sub>-IR as a fresh approach for the therapy of ND. |
| first_indexed | 2024-03-10T03:45:09Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:45:09Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-23e5cfa47c79414eb18f2f525aa638242023-11-23T11:22:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310540810.3390/ijms23105408Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06Andrea Bagán0José A. Morales-García1Christian Griñán-Ferré2Caridad Díaz3José Pérez del Palacio4Maria C. Ramos5Francisca Vicente6Belén Pérez7José Brea8María Isabel Loza9Mercè Pallàs10Carmen Escolano11Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, SpainThe Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Department of Cell Biology, School of Medicine, Complutense University (UCM), 28040 Madrid, SpainPharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, University of Barcelona, 08028 Barcelona, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Avda. del Conocimiento 34, 18016 Armilla, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Avda. del Conocimiento 34, 18016 Armilla, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Avda. del Conocimiento 34, 18016 Armilla, SpainFundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Avda. del Conocimiento 34, 18016 Armilla, SpainDepartment of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, 08193 Barcelona, SpainInnopharma Screening Platform, BioFarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15706 Santiago de Compostela, SpainInnopharma Screening Platform, BioFarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15706 Santiago de Compostela, SpainPharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neurociències, University of Barcelona, 08028 Barcelona, SpainLaboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, 08028 Barcelona, SpainThe 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<sub>2</sub> receptors (I<sub>2</sub>-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I<sub>2</sub>-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 I<sub>2</sub>-IR as a fresh approach for the therapy of ND.https://www.mdpi.com/1422-0067/23/10/5408imidazoline I<sub>2</sub> receptor ligandpharmacokineticsbicyclic α-iminophosphonatemetabolic profileneuroprotectionAlzheimer’s disease |
| spellingShingle | Andrea Bagán José A. Morales-García Christian Griñán-Ferré Caridad Díaz José Pérez del Palacio Maria C. Ramos Francisca Vicente Belén Pérez José Brea María Isabel Loza Mercè Pallàs Carmen Escolano Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06 International Journal of Molecular Sciences imidazoline I<sub>2</sub> receptor ligand pharmacokinetics bicyclic α-iminophosphonate metabolic profile neuroprotection Alzheimer’s disease |
| title | Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06 |
| title_full | Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06 |
| title_fullStr | Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06 |
| title_full_unstemmed | Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06 |
| title_short | Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I<sub>2</sub> Receptor Ligand B06 |
| title_sort | insights into the pharmacokinetics and in vitro cell based studies of the imidazoline i sub 2 sub receptor ligand b06 |
| topic | imidazoline I<sub>2</sub> receptor ligand pharmacokinetics bicyclic α-iminophosphonate metabolic profile neuroprotection Alzheimer’s disease |
| url | https://www.mdpi.com/1422-0067/23/10/5408 |
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