ff4fdd861db0f9a4dc3cee6a9e8bb18b ijms-23-05408-v3_1_.pdf a984421959e1cfda3929e2cdb82e8fef1c19af75 ijms-23-05408-v3_1_.pdf ead6876a6cc37fabb3a5c280b0259fc62e5421ab1f7133e3ed1719848c9c86f6 ijms-23-05408-v3_1_.pdf Title: Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06 Subject: 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 -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: imidazoline I2 receptor ligand; pharmacokinetics; bicyclic -iminophosphonate; metabolic profile; neuroprotection; Alzheimer’s disease; Parkinson’s disease 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 and Carmen Escolano Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri May 13 12:32:34 2022 CEST ModDate: Fri May 20 02:57:00 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2152303 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JFLFCJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 EUNBMT+VnURWPalladioL Type 1 Custom yes yes no 15 0 ZZJXSH+EURM10 Type 1 Builtin yes yes no 19 0 CUFERW+URWPalladioL-Bold Type 1 Custom yes yes no 23 0 KYLHEQ+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 NSUCKC+URWPalladioL-Ital Type 1 Custom yes yes no 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 50 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi 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Chemical Synthesis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: In Vitro Study of the Role of B06 in a Cellular Model of Neurodegeneration Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Children: Item: Title: SH-SY5Y Human Cell Line Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: Primary Glial Cultures Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Cell Viability Assay and Apoptosis Measurement Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Nitrites Measurement Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: Method Validation for Quantification of B06 in Mouse Plasma and Mouse Brain Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: In Vivo Pharmacokinetics of B06 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Children: Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Item: Title: Calibration Curve for B06 in Plasma Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: Quantitation for B06 in Plasma Samples at Dose 10 mg/kg and Samples Grouping and Statistics in Plasma Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: Calibration Curve for B06 in Brain Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Item: Title: Quantitation for B06 in Brain Samples at Dose 10 mg/kg and Samples Grouping and Statistics in Brain Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4a87761d Item: Title: Metabolic Profiling In Vivo of B06 Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@66d1af89 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@8646db9 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@37374a5e Item: Title: Patents Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4671e53b Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@2db7a79b Info: Title: Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06 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 and Carmen Escolano Subject: 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 -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. 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