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.