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

Abstract

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

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

“…The compounds were prepared using our previously optimized conditions [34]. I 2 -IR pKi for MCR5 and MCR9 were determined as 9.42±0.16 nM and 8.85±0.21 nM, respectively, showing that both compounds also had high selectivity against α 2 adrenergic receptors (457 and 1862, respectively) [35].…”

“…Selective I 2 -IR ligands induce hypothermia in rodents [4]. In particular, the hypothermic effect of compound MCR5 in mice was evaluated in a recent study from our research group (results for compound 2c in ref 35) [35]. Similar to MCR5, MCR9 induced mild hypothermia as assessed by a moderate reduction (-2.3°C) in rectal temperature 1 h after injection at the tested dose of 20 mg/kg in adult CD-1 mice and as compared with vehicle-treated controls (Fig.…”

“…The experimental synthetic conditions fulfill the principles of green chemistry, giving access to novel compounds with high selectivity and affinity for I 2 -IR. Among them, we tested MCR5 [diethyl (1-(3-chloro-4fluorobenzyl)-5,5-dimethyl-4-phenyl-4,5-dihydro-1Himidazol-4-yl)phosphonate] in a previous work to demonstrate its neuroprotective and analgesic effects, and it showed promising results in models of brain damage [35]. In particular, mechanisms of neuroprotection related to regulating apoptotic pathways or inhibiting p35 cleavage mediated by this new active compound have been found.…”

Imidazoline I 2 receptors: An update

“…X. Li & Zhang, 2011). Several other synthetic I 2 receptor ligands are described more recently in a preliminary manner and are not included, including a recent study that described a new family of (2-imidazolin-4-yl) phosphonates that had high affinity to I 2 receptors (Abas et al, 2017). Among these, several compounds have been frequently used in the literature to explore the pharmacological effects related to I 2 receptors and becoming invaluable research tools, such as 2-BFI, BU224, phenyzoline and CR4056.…”

“…The hypothermic effect was nearly fully reversed by a pretreatment with idazoxan, but not by the imidazoline I 1 receptor antagonist efaroxan or the α 2 -adrenoceptor antagonist yohimbine, suggesting that I 2 receptors primarily mediate the observed hypothermia (Thorn et al, 2012). Given the relatively simple and quick nature of hypothermia measurement, this measure, together with antagonism tests, could serve as a preliminary in vivo bioassay to develop and discover novel I 2 receptor ligands (Abas et al, 2017). In addition, because hypothermia is well known to have beneficial effect in cerebral ischemia and can cause significant neuroprotection even with a small body temperature drop (Craven & Conway, 1997), I 2 receptor ligands-induced hypothermia may partially contribute to their neuroprotective activity (Craven & Conway, 1997).…”