Pharmacology, Medicinal Chemistry, and Therapeutic Potential of Imidazoline Receptor Ligands

The imidazoline receptor (IR) system, comprising the I 1 R, I 2 R, and I 3 R subtypes, consists of binding sites involved in cardiovascular, metabolic, and neurological disorders. This review updates the 2004 compilation by Dardonville and Rozas on IR ligands, emphasizing promising ligands, subtype selectivity, and pharmacological profiling. Representative ligands for each subtype are analyzed to highlight key pharmacological aspects, including affinity, selectivity, and functional activity, integrating findings from preclinical and clinical studies. Critical molecular targets such as Nischarin/IRAS for I 1 R and MAO‐B–associated sites for I 2 R are discussed in the context of ligand design and CNS penetration. I 1 R‐selective ligands, exemplified by rilmenidine, show improved selectivity over α 2 ‐adrenoceptors and exhibit antihypertensive, metabolic, and neuroprotective effects. I 2 R ligands display neuroprotective, anti‐inflammatory, and analgesic activities, with CR4056 progressing to Phase II trials. PET imaging with [ 11 C]BU99008 has validated I 2 R upregulation as a biomarker for neurodegeneration. Overall, the IR system presents therapeutic opportunities: I 1 R for cardiovascular and metabolic disorders, I 2 R for pain and neurodegeneration, and I 3 R for diabetes. Continued ligand optimization and receptor characterization are essential for clinical translation.