title: Neuroprotective Effects of a Structurally New Family of High Affinity Imidazoline I2Receptor Ligands.
abstract: The imidazoline I2receptors (I2-IRs) are widely distributed in the brain, and I2-IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I2-IR remains unknown, the discovery of selective I2-IR ligands devoid of α2-adrenoceptor (α2-AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2-imidazolin-4-yl)phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I2-IRs than idazoxan, and high I2/α2selectivity. In vivo studies in mice showed that acute treatments with 1b and 2c significantly increased p-FADD/FADD ratio (an index of cell survival) in the hippocampus when compared with vehicle-treated controls. Additionally, acute and repeated treatments with 2c, but not with 1b, markedly reduced hippocampal p35 cleavage into neurotoxic p25. The present results indicate a neuroprotective potential of (2-imidazolin-4-yl)phosphonates acting at I2-IRs.
authors.affiliation: Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona , Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Abás
authors.affiliation: Department of Pharmacology, University of the Basque Country, UPV/EHU , E-48940 Leioa, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM.
authors.forename: Amaia M
authors.initials: AM
authors.lastname: Erdozain
authors.affiliation: Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB) , Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Keller
authors.affiliation: Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona , Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodríguez-Arévalo
authors.affiliation: Department of Pharmacology, University of the Basque Country, UPV/EHU , E-48940 Leioa, Bizkaia, Spain.|Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.affiliation: Laboratory of Neuropharmacology, IUNICS/IdISPa, University of the Balearic Islands (UIB) , Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain.
authors.forename: Jesús A
authors.initials: JA
authors.lastname: García-Sevilla
authors.affiliation: Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona , Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
authors.forename: Carmen
authors.identifier: 0000-0002-9117-8239
authors.initials: C
authors.lastname: Escolano
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D054755:Imidazoline Receptors / Q000819:agonists*; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D054755:Imidazoline Receptors; D048288:Imidazolines; D008024:Ligands; D018696:Neuroprotective Agents; C487767:imidazoline receptor 2
keywords: (2-Imidazolin-4-yl)phosphonates; imidazoline I2 receptors; neuroprotection