Imidazoline Binding Sites

Various compounds that possess an imidazoline or guanidinium moiety, along with a number of chemically related compounds, elicit a variety of pharmacological effects on cardiovascular/cerebrovascular function, metabolism, insulin secretion and ion transport. These compounds include the α2-adrenoceptor agonists clonidine, rilmenidine, moxonidine and guanabenz, the α1-adrenoceptor agonist/α2-adrenoceptor antagonist cirazoline, the α2-adrenoceptor antagonist idazoxan, the ion transport inhibitor amiloride and other structurally related ligands. Although such ligands interact with known receptor systems, some of their functional effects, such as their centrally-mediated effects on blood pressure and their ability to augment glucose-induced insulin secretion from pancreatic β cells, are pharmacologically ill-defined. Indeed, several studies indicate that these molecules interact with distinct imidazoline binding sites. These sites share the common property of not recognizing endogenous agonists for known monoamine receptors and exhibiting high affinity for selected compounds containing an imidazoline, guanidinium or structurally-related substituent.

Radioligand binding and photo-affinity labeling studies indicate that imidazoline binding sites represent a heterogenous family of proteins that are currently grouped as I1 and I2. The two groups of binding sites differ in their ligand recognition properties, tissue distribution and possibly their localization within the cell. I1 binding sites have been associated with diacylglycerol or cAMP generation and are implicated in the centrally-mediated effects of imidazoline ligands on blood pressure. However, their primary structure has yet to be established and their precise functional role remains controversial. Very recently, highly selective ligands for I1 binding proteins, as compared with their activities at α2-adrenoceptors and I2 binding sites, have been synthesized. These ligands include LNP 911, its radio iodinated analog [125I]- LNP 911 and the photo-affinity azido-derivative LNP 906. Binding studies using [125I]- LNP 911 showed that this radioligand clearly discriminates I1 binding sites from both I2 binding sites and α2-adrenoceptors.

With respect to the I2 subgroup of imidazoline binding proteins, evidence suggests that one member of this family is identical to the B isoform of the enzyme monoamine oxidase (MAO). However, the imidazoline binding domain on MAO is distinct from the enzyme active site that recognizes the mechanism-based inhibitors and it is not equally accessible in all tissues. At present, the role of I2 binding sites in the regulation of MAO activity is still uncertain.

In addition to I1 and I2 imidazoline binding sites, a third site referred to as the I3 site, has been reported in pancreatic β cells. The I3 binding site displays ligand-recognition properties that differ from those of the other imidazoline binding proteins and appears to be involved in regulation of insulin secretion.

Current research in this area is also focused on the identification of putative endogenous ligands for imidazoline binding sites. Although agmatine was originally suggested as a potential candidate, subsequent studies have refuted these earlier claims. Specific endogenous β-carbolines have also been proposed as ligands for some imidazoline binding sites, which is of interest as earlier data in the literature suggested a role for β-carbolines as endogenous regulators of MAO. More recently, it has been reported that imidazoleacetic acid-ribotide may be a potential endogenous ligand for I1 and I3 binding sites.


The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Currently Accepted Name I1 I2 I3
Alternate Names I1 Imidazole binding site
I1 Imidazoline receptor
IGRS - imidazoline/guanidinium receptive site,
non-adrenergic imidazoline- preferring binding sites, idaxozan (I) receptors
I3 Imidazoline receptor
Ligands Clonidine (C7897)
Cirazoline (C223)
Benazoline (B4555)
Moxonidine (M1559)
Efaroxan (E3263)
Rilmenidine (R134)
Cirazoline (C223)
Amiloridea (A7410)
Guanabenz (G110)
Metrazoline (M5685)
Benazoline (B4555)
Idazoxan (I6138)
BU224 (B154)
2-BFI (RX 801077)a
Efaroxan (E3263)
Idazoxan (I6138)
Putative Endogenous Ligands Agmatine (A7127)
Harmane (103276)
Imidazoleacetic acid-ribotide
Not Known
Imidazoleacetic acid-ribotide
Radioligands of Choice [3H]-Clonidineb
[3H]-2-BFI a
Not Known
Tissue Expression Brain, kidney, heart Brain, kidney, liver, adipose tissue Pancreatic β cells
Physiological Function Sympathetic and cardiovascular functions Regulation of monoamine turnover Stimulation of insulin secretion; glycaemia control
Disease Relevance Hypertension, cardiac arrhythmias, congestive heart failure Mood disorders Type II diabetes



a) The imidazoline binding domains on MAO-A and MAO-B exhibit distinct ligand recognition properties. Idazoxan, BU224 and 2-BFI exhibit higher affinity for the imidazoline binding domain on MAO-B. Amiloride exhibits higher affinity for the imidazoline binding domain on MAO-A. Nomenclature for subtypes of I2 imidazoline binding sites is unresolved.

b) For identification of imidazoline binding sites, these radioligands are commonly used in the presence of 10 µM rauwolscine or epinephrine to block binding to α2-adrenoceptors.



[125I]-AMIPI: 2-[3-Amino-4-[125I]iodophenoxyl]methyl imidazoline
[125I]-AZIPI: 2-[3-Azido-4-[125I]iodophenoxyl]methyl imidazoline
2-BFI: 2-(2-Benzofuranyl)-2-imidazoline
BL11282: 5-Chloro-3-(4,5-dihydro-1H-imidazol-2-yl)-2-methylindole
BU224: 2-(4,5-Dihydroimidaz-2-yl)-quinoline
LNP 509: 2-(Dicyclopropylmethylamino)-4,5-dimethyl-pyrroline
LNP 911: 2-(2-Chloro-4-iodo-phenylamino)-5-methyl-pyrroline
LNP 906: (5-Azido-2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline
RX871024: 2-(N-Phenyl-indoyl)imidazole hydrochloride
S23515: 2-Amino-5-(2-Bromo-phenoxymethyl)-oxazoline
S23757: 2-(2-Fluoro-5-methyl-phenyl)-imidazoline


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