Neuroprotective Effects of a Structurally New Family of High Affinity Imidazoline I2 Receptor Ligands

Abstract

The imidazoline I₂ receptors (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/α₂ selectivity. 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.

Keywords: (2-Imidazolin-4-yl)phosphonates; imidazoline I2 receptors; neuroprotection.