Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 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 I2 receptors (I2-IR) that are widely distributed in the brain and are altered in patients with brain dis...
| Autores: | , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Santiago de Compostela (USC) |
| Repositorio: | Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela |
| Idioma: | inglés |
| OAI Identifier: | oai:minerva.usc.gal:10347/45126 |
| Acceso en línea: | https://hdl.handle.net/10347/45126 |
| Access Level: | acceso abierto |
| Palabra clave: | Imidazoline I2 receptor ligand Pharmacokinetics Bicyclic α-iminophosphonate Metabolic profile Neuroprotection Alzheimer’s disease Parkinson’s disease |
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Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06Bagán Polonio, AndreaMorales García, José A.Griñán Ferré, ChristianDíaz Navarro, CaridadPérez del Palacio, JoséRamos Martín, Maria CarmenVicente Pérez, FranciscaPérez Fernández, BelénBrea Floriani, José ManuelLoza García, María IsabelPallàs Lliberia, MercèEscolano Mirón, CarmenImidazoline I2 receptor ligandPharmacokineticsBicyclic α-iminophosphonateMetabolic profileNeuroprotectionAlzheimer’s diseaseParkinson’s diseaseThe 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 NDMDPIUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS)Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica20222022-05-1220222022-05-12journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10347/45126reponame:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostelainstname:Universidad de Santiago de Compostela (USC)InglésengAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2019-107991RB-I00 REACCIONES MULTICOMPONENTE: DESCUBRIMIENTO, DEASARROLLO Y APLICACIONES EN BIOMEDICINAAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2019-106285RB MODULACION DE LA EPOXIDO HIDROLASA SOLUBLE (SEH) EN CEREBRO Y TEJIDOS PERIFERICOS: PAPEL DEL EJE INTESTINO-CEREBRO EN LA NEURODEGENERACIONopen accesshttp://purl.org/coar/access_right/c_abf2© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:minerva.usc.gal:10347/451262026-06-15T12:47:27Z |
| dc.title.none.fl_str_mv |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| title |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| spellingShingle |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 Bagán Polonio, Andrea Imidazoline I2 receptor ligand Pharmacokinetics Bicyclic α-iminophosphonate Metabolic profile Neuroprotection Alzheimer’s disease Parkinson’s disease |
| title_short |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| title_full |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| title_fullStr |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| title_full_unstemmed |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| title_sort |
Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligand B06 |
| dc.creator.none.fl_str_mv |
Bagán Polonio, Andrea Morales García, José A. Griñán Ferré, Christian Díaz Navarro, Caridad Pérez del Palacio, José Ramos Martín, Maria Carmen Vicente Pérez, Francisca Pérez Fernández, Belén Brea Floriani, José Manuel Loza García, María Isabel Pallàs Lliberia, Mercè Escolano Mirón, Carmen |
| author |
Bagán Polonio, Andrea |
| author_facet |
Bagán Polonio, Andrea Morales García, José A. Griñán Ferré, Christian Díaz Navarro, Caridad Pérez del Palacio, José Ramos Martín, Maria Carmen Vicente Pérez, Francisca Pérez Fernández, Belén Brea Floriani, José Manuel Loza García, María Isabel Pallàs Lliberia, Mercè Escolano Mirón, Carmen |
| author_role |
author |
| author2 |
Morales García, José A. Griñán Ferré, Christian Díaz Navarro, Caridad Pérez del Palacio, José Ramos Martín, Maria Carmen Vicente Pérez, Francisca Pérez Fernández, Belén Brea Floriani, José Manuel Loza García, María Isabel Pallàs Lliberia, Mercè Escolano Mirón, Carmen |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CiMUS) Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica |
| dc.subject.none.fl_str_mv |
Imidazoline I2 receptor ligand Pharmacokinetics Bicyclic α-iminophosphonate Metabolic profile Neuroprotection Alzheimer’s disease Parkinson’s disease |
| topic |
Imidazoline I2 receptor ligand Pharmacokinetics Bicyclic α-iminophosphonate Metabolic profile Neuroprotection Alzheimer’s disease Parkinson’s disease |
| 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 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 |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-05-12 2022 2022-05-12 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10347/45126 |
| url |
https://hdl.handle.net/10347/45126 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2019-107991RB-I00 REACCIONES MULTICOMPONENTE: DESCUBRIMIENTO, DEASARROLLO Y APLICACIONES EN BIOMEDICINA Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2019-106285RB MODULACION DE LA EPOXIDO HIDROLASA SOLUBLE (SEH) EN CEREBRO Y TEJIDOS PERIFERICOS: PAPEL DEL EJE INTESTINO-CEREBRO EN LA NEURODEGENERACION |
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open access http://purl.org/coar/access_right/c_abf2 http://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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application/pdf |
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MDPI |
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MDPI |
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