Probes for imidazoline binding sites: synthesis and evaluation of a selective, irreversible I 2 ligand (original) (raw)
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I2-Imidazoline Binding Site Affinity of a Structurally Different Type of Ligands
Bioorganic & Medicinal Chemistry, 2002
Two families of compounds with affinity towards the I(2) imidazoline binding sites are reported. The first is a family of compounds structurally related to agmatine with two guanidine or 2-aminoimidazoline groups at each end of an aliphatic chain of six, eight, nine or 12 methylene groups. Second, and following the model of clonidine, we propose another family of compounds also with two guanidine or 2-aminoimidazoline groups at each end of a chain consisting of two phenyl rings connected by groups such as CH(2), CO, NH and SO(2). The affinity of the compounds towards the I(2) imidazoline binding sites was then evaluated in human brain tissues. In order to determine their pharmacological selectivity versus alpha(2)-adrenoceptors, the affinity for these receptors was also evaluated for the compounds with the highest affinities at I(2) imidazoline binding sites. The results obtained show that many of the compounds exhibit a considerable affinity towards the I(2) imidazoline binding sites. The aliphatic derivatives, in particular, present a very interesting selectivity for the I(2) imidazoline binding sites versus the alpha(2) adrenoceptors. To better understand these findings, mono-guanidinium analogues of the aliphatic derivatives were synthesised and tested showing poor affinity for I(2) imidazoline binding sites. The importance of these results lies in the novelty of the chemical structures studied (dicationic aliphatic compounds particularly) because they are significantly different to those of the I(2) imidazoline binding site ligands reported to date.
Identification of ligands selective for central I 2-imidazoline binding sites
Neurochemistry International, 1997
Using radioligand binding techniques, several compounds selective for mammalian brain imidazoline2 receptors have been identified. In rabbit brain membranes, a series of 6 and/or 7 aromatic-substituted derivatives of the α2-adrenoceptor antagonist idazoxan were found to show moderate affinity for I2 receptors over α2-adrenoceptos, in particular 6,7-dichlorodazoxan, which was 41 fold selective in favour of I2 receptors. Modification of the benzodioxan
Journal of Medicinal Chemistry, 2008
The study of two series of 2-aryl-ethylen-imidazolines 3-7 and 8-12 inspired by I 2-IBS ligands phenyzoline (1) and diphenyzoline (2), respectively, confirmed the interesting "positive" or "negative" morphine analgesia modulation displayed by their corresponding leads and demonstrated that these effects might be correlated with morphine tolerance and dependence, respectively. By comparative examination of rationally designed compounds, some analogies between binding site cavity of I 2-IBS proteins and R 2C-adrenoreceptor emerged.
Molecular pharmacology, 1994
Imidazoline/guanidinium receptive sites (IGRS) are membrane proteins that exhibit high affinity for various compounds with an imidazoline or guanidinium moiety. The structure of these binding sites and their significance in the broad pharmacological action of such ligands are unclear. To address this issue, we developed selective high affinity compounds that could be radioiodinated and used as molecular probes for structural characterization of these proteins. This report describes the synthesis and characterization of such a molecule, 2-(3-amino-4-[125I]iodophenoxy)methylimidazoline ([125I]AMIPI). [125I]AMIPI is structurally related to cirazoline, an imidazoline exhibiting high affinity for IGRS and the family of related imidazoline binding sites. The phenyl-substituted analogue of cirazoline, 2-(3-aminophenoxy)methylimidazoline, was generated by alkylation of acetamidophenol with 2-chloromethylimidazoline. 2-(3-Aminophenoxy)methylimidazoline exhibited high affinity for IGRS in rab...
ACS chemical neuroscience, 2017
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 ...
Further biochemical characterization of imidazoline binding sites from the human brainstem
Fundamental & Clinical Pharmacology, 1997
Biochemical characteristics of imidazoline specific binding sites from the human brainstem were further investigated using ['Hlidazoxan as radiolabeled ligand. The study of the interaction of [3H]idazoxan binding sites with heparin and lectins (soybean and lentil lectin) confirm the heterogeneity of these sites in the human brain. In fact, about 10-158 of [3H]idazoxan binding sites were retained by each of the three supports used, leading to the hypothesis that two populations of sites, with different biochemical characteristics, coexist in this tissue. A small proportion of [3H]idazoxan binding sites was retained on an affinity chromatography support consisting of a clonidine-derived Pharmalink column. The binding activity of these clonidine-eluted sites was markedly and dose-dependently improved by the addition of 'treated fall-through' fraction from the same column. On the other hand, this 'treated fall-through' fraction inhibited the binding activity detected in the solubilized human brainstem membranes. These results also suggest the existence of heterogeneous imidazoline specific binding sites in the human brainstem and the existence of endogenous factors able to discriminate between them. human brain / imidazoline 1 idazoxan I binding sites
Molecular Pharmacology, 2002
The I 1 subtype of imidazoline receptors (I 1 R) is a plasma membrane protein that is involved in diverse physiological functions. Available radioligands used so far to characterize the I 1 R were able to bind with similar affinities to ␣ 2 -adrenergic receptors (␣ 2 -ARs) and to I 1 R. This feature was a major drawback for an adequate characterization of this receptor subtype. New imidazoline analogs were therefore synthesized and the present study describes one of these compounds, 2-(2-chloro-4-iodophenylamino)-5-methyl-pyrroline (LNP 911), which was of high affinity and selectivity for the I 1 R. LNP 911 was radioiodinated and its binding properties characterized in different membrane preparations. Saturation experiments with [ 125 I]LNP 911 revealed a single high affinity binding site in PC-12 cell membranes (K D ϭ 1.4 nM; B max ϭ 398 fmol/mg protein) with low nonspecific binding.
Pharmacological characterization of I1 and I2 imidazoline receptors in human striatum
Neurochemistry International, 1997
Abstraet--[3H]RX821002, [3H]clonidine and [aH]idazoxan have previously been shown to selectively label ~2-adrenergic receptors, 11 and I2 imidazoline receptors in the human central nervous system, respectively. Idazoxan shows relatively high affinity for all three receptors. We investigated the possible selectivity of several compounds towards one of those receptors in human striatum. Addition of an alkoxy group at the 2-position of the benzodioxan moiety of idazoxan (ethoxy-idazoxan, methoxy-idazoxan) increases the ct2selectivity in human brain. Efaroxan is also ~t2-selective. On the contrary, BU224, BU239, cirazoline and RX801077 display imidazoline receptor selectivity. Our results indicate that for all molecules tested, idazoxan and 'flat' analogs possess 11/I 2 receptor selectivity. A 'bulky' substituent at the 2-position of the benzodioxan ring gives rise to ct2-adrenergic receptor selectivity. Until now, we found no more than 3-fold difference in IC50 between both imidazoline receptors. Both receptors also display similar stereoselectivity, suggesting that they might be 'interconnected' in the human striatum.