Imidazoline Receptor System: The Past, the Present, and the Future

Imidazoline receptors historically referred to a family of nonadrenergic binding sites that recognize compounds with an imidazoline moiety, although this has proven to be an oversimplification. For example, none of the proposed endogenous ligands for imidazoline receptors contain an imidazoline moiety but they are diverse in their chemical structure. Three receptor subtypes (I₁, I₂, and I₃) have been proposed and the understanding of each has seen differing progress over the decades. I₁ receptors partially mediate the central hypotensive effects of clonidine-like drugs. Moxonidine and rilmenidine have better therapeutic profiles (fewer side effects) than clonidine as antihypertensive drugs, thought to be due to their higher I₁/α₂-adrenoceptor selectivity. Newer I₁ receptor agonists such as LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride] have little to no activity on α₂-adrenoceptors and demonstrate promising therapeutic potential for hypertension and metabolic syndrome. I₂ receptors associate with several distinct proteins, but the identities of these proteins remain elusive. I₂ receptor agonists have demonstrated various centrally mediated effects including antinociception and neuroprotection. A new I₂ receptor agonist, CR4056 [2-phenyl-6-(1H-imidazol-1yl) quinazoline], demonstrated clear analgesic activity in a recently completed phase II clinical trial and holds great promise as a novel I₂ receptor–based first-in-class nonopioid analgesic. The understanding of I₃ receptors is relatively limited. Existing data suggest that I₃ receptors may represent a binding site at the Kir6.2-subtype ATP-sensitive potassium channels in pancreatic β-cells and may be involved in insulin secretion. Despite the elusive nature of their molecular identities, recent progress on drug discovery targeting imidazoline receptors (I₁ and I₂) demonstrates the exciting potential of these compounds to elicit neuroprotection and to treat various disorders such as hypertension, metabolic syndrome, and chronic pain.