Imidazoline Receptor

There is now general acceptance that there are three main imidazoline receptor classes, the I1 imidazoline receptor which mediates the sympatho-inhibitory actions to lower blood pressure, the I2 receptor which is an important allosteric binding site of monoamine oxidase and the I3 receptor which regulates insulin secretion from pancreatic beta cells. Thus all three represent important targets for cardiovascular research.

BU 226 hydrochloride
BU 239 hydrochloride
BU 224 hydrochloride
Agmatine sulfate
2-BFI hydrochloride


Discovery of the I1 imidazoline receptor

The concept that imidazoline agonists act on a novel receptor in addition to their well-known actions on α2AR was originally based on in vivo structure-activity studies. The existence of a novel imidazoline receptor was first proposed to account for differential responses to imidazoline and phenylethylamine α2AR agonists. In the same year, Atlas & Burstein claimed the existence of a natural ligand for clonidine-like drugs that was neither a catecholamine or a peptide. Radioligand binding techniques have substantiated the existence of imidazoline-specific binding sites labeled by [3H] clonidine. In addition, the hypotensive action of clonidine-like compounds in the ventral medulla was positively correlated with affinity at the imidazoline-binding site and not for the α2AR binding site. There are over 1000 reports supporting the notion that the I1R is a distinctive receptor with specific functions. Furthermore, the I1R is included in the receptor list of the international union of pharmacology.

Identification of imidazoline receptor subtypes

It is now accepted that there are at least two subtypes of imidazoline receptors, the I1 and I2 subtypes, and possibly a third I3 subtype. The I1R subtype are characterized by a high affinity for a group of agents which act in the brainstem to lower blood pressure, including clonidine, rilmenidine and moxonidine. The I2R subtype shows lower affinity for these antihypertensives with a central nervous system site of action but higher affinity for other imidazolines and guanidines, and represents a novel recognition site on mitochondrial monoamine oxidase. The proposed I3R is found so far exclusively in the pancreatic islets and appears to closely resemble the I1R in ligand specificity, with the primary difference being the relative efficacy of different agents.

I1R imidazoline receptor signal transduction

The predominant cellular model for investigation of I1R signaling pathways has been pheochromocytoma cells (PC12). These adrenal tumor cells express I1R but lack α2AR, as shown by radioligand binding as well as molecular approaches. Stimulation of the I1R in PC12 cells with the agonist moxonidine leads to activation of phosphatidylcholine selective phospholipase C (PC-PLC). Activationof PC-PLC is characteristic of the signaling pathways coupled to certain cytokine receptors, including some of the interleukin receptors, and also mediates some of the actions of thromboxanes in astrocytes. Activation of PC-PLC by imidazoline agonists results in increased formation of the second messenger diacylglyceride (DAG) from phosphatidylcholine and the release of phosphocholine. These effects can be blocked by both efaroxan, an I1R antagonist, and by D609, an inhibitor of PC-PLC.

DAG commonly activates several isoforms of PKC. A common (cPKCβ11) and an atypical PKC isoform enzymatic activity were increased after moxonidine treatment in PC12 cells. APKC also showed subcellular relocalization, with activity in the cytosol decreasing and membrane fraction increasing. Two members of the MAPK family of kinase cascades, ERK and JNK, were activated by moxonidine in PC12 cells. Moxonidine stimulated the phosphorylated form of ERK 1.5-fold and JNK activity was elevated two-fold. The activation of both kinases was dose-dependent. The dose-response relationships for I1R receptor activation of arachidonic acid release, prostaglandin production and DAG accumulation. A concentration-dependent increase in cell number was also induced by a 2-day treatment with the I1R agonist clonidine in PC12 cell. These results imply a slight mitogenic action of I1R activation. ERK activation was receptor-mediated, because it was blocked with efaroxan.

These results suggest that the I1R may resemble cytokine receptors such as those for interleukins 1 and 3, which activate a similar. Recently, the I1R in PC12 cells was reported to be negatively linked to the cAMP pathway, via a pathway independent of the pertussis toxin-sensitive G-protein that is utilized by the α2AR. Thus, the I1R seems to be negatively coupled to the cAMP pathway, which may be downstream from PC-PLC activation or arachidonic acid release.


Velliquette, R. A. (2003). In Vivo Metabolic Pharmacology of Imidazoline Receptors (Doctoral dissertation, Case Western Reserve University).