Imidazoline I₂ receptors: An update

Since first introduced more than two decades ago, the research in imidazoline I₂ receptors has been steadily increasing. This review provides an update on the current status of I₂ receptor pharmacology. Imidazoline I₂ receptors or I₂ binding sites refer to several (at least four) different proteins that bind to [³H]-idazoxan and [³H]-2-BFI with high affinity. The molecular identities of the proteins remain elusive. One of the proteins (45kD) seems to be consistent with the identity of brain creatine kinase. The biological functions of I₂ receptors have been primarily unveiled by the studies of selective I₂ receptor ligands. Accumulating evidence suggests that I₂ receptor ligands are effective analgesics for persistent and chronic painful conditions such as inflammatory, neuropathic and postoperative pain. One selective I₂ receptor ligand, CR4056, has been advanced to phase II clinical trial with the therapeutic indication of chronic inflammatory pain (osteoarthritis). The expansion to the treatment of other chronic pain conditions should be expected if CR4056 could eventually be approved as a new drug. I₂ receptor ligands also demonstrate robust discriminative stimulus activity and induce a characteristic discriminative cue in animals. Biochemical and preclinical in vivo investigations also suggest that I₂ receptor ligands have neuroprotective activity and modulate body temperature. The emerging discrepancies of a range of purported selective I₂ receptor ligands suggest different pharmacological effects mediated by discrete I₂ receptor components which likely attribute to the I₂ receptor-related proteins. It is proposed that the I₂ receptors represent an emerging drug target for the treatment of neurological disorders such as pain and stroke, and deserve more research attention to translate preclinical findings to pharmacotherapies.