Neuroprotective Effects of a Structurally New Family of High Affinity Imidazoline I 2 Receptor Ligands.

The imidazoline I ₂ receptors (I ₂ -IRs) are widely distributed in the brain, and I ₂ -IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I ₂ -IR remains unknown, the discovery of selective I ₂ -IR ligands devoid of α ₂ -adrenoceptor (α ₂ -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 I ₂ -IRs than idazoxan, and high I ₂ /α ₂ 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 I ₂ -IRs.