Eglumegad

Eglumegad (LY-354,740) is a research drug developed by Eli Lilly, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.

Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR2/3). A substantial D2 dopaminergic component was also found.

In experiments on mice, eglumegad was found to be as effective as diazepam for treating anxiety symptoms in several standard tests, but without producing any of the negative side effects of diazepam such as sedation and memory impairment. Tests in humans confirmed that it produced anxiolytic effects without producing sedation. However it did slightly reduce cognitive performance in tests on monkeys.

Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine and morphine in animals, as well as inhibiting the development of tolerance to morphine, raising hope that this drug may be useful for treating drug addiction in humans.

Eglumegad and related drugs are neuroprotective and are synergistic with the neuroprotection produced by NMDA antagonist drugs, which may make these drugs useful in aiding recovery from brain injury.

This class of drugs also interacts with hallucinogenic drugs, with eglumegad reducing the effects of 5HT2A agonist hallucinogens, while conversely the mGluR2/3 antagonist LY-341,495 increased the behavioural effects of these drugs. This suggests that mGluR2/3 agonists such as eglumegad may have potential uses in the treatment of some forms of psychosis, although eglumegad had only limited effects on the action of the dissociative drug phencyclidine which is generally a better model for schizophrenia than the 5HT2A agonist hallucinogens.

Development of this drug is continuing, with several clinical trials completed and more planned. Poor oral bioavailability of the original formulation led to limited efficacy in the initial human trials, and so the prodrug form LY-544,344 looks more likely to be the final canditate for aspired marketing.