Eglumetad (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

; also known as eglumegad) is a research drug developed by

Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...

, which is being investigated for its potential in the treatment of

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

and drug addiction. It is a

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...

derived compound and its mode of action implies a novel mechanism.

Mechanism of action

Eglumetad acts as a group-selective agonist for the group II metabotropic glutamate receptors ( mGluR₂_/ ₃). It is unclear whether eglumetad directly interacts with dopamine D2 receptors.

Effects

In experiments on mice, eglumetad was found to be as effective as

diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...

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. Eglumetad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

and

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

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. Eglumetad and related drugs are neuroprotective and are synergistic with the neuroprotection produced by ''N''-Methyl-D-aspartic acid (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 eglumetad reducing the effects of 5HT_2A agonist hallucinogens, while conversely the mGluR_2/3 antagonist

LY341495 LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors ( mGluR2/3). It is used in scientific research in severa ...

increased the behavioural effects of these drugs. This suggests that mGluR_2/3 agonists such as eglumetad 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 Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptio ...

which is generally a better model for schizophrenia than the 5HT_2A agonist hallucinogens. Eglumetad also interferes in the

hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a ...

, with chronic oral administration of this drug leading to markedly reduced baseline

cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal cortex in the adrenal gland ...

levels in bonnet macaques (

Macaca radiata The bonnet macaque (''Macaca radiata''), also known as zati,Chambers English Dictionary is a species of macaque endemic to southern India. Its distribution is limited by the Indian Ocean on three sides and the Godavari and Tapti Rivers, along wi ...

); acute infusion of eglumetad resulted in a marked diminution of

yohimbine Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree ''Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2- ...

-induced

stress response The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...

in those animals. In human adrenocortical cells, eglumetad has been shown to down-regulate intracellular

cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(cAMP) and

steroidogenesis A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

, with a significant decrease in

aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

and cortisol production.

Clinical development

Development of this drug and related compounds 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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

form LY544344 did seem to be a more likely drug candidate for further development. However a clinical trial of LY544344 was discontinued early based on findings of convulsions in preclinical studies.

References

{{Metabotropic glutamate receptor modulators Anxiolytics Amino acids Eli Lilly and Company brands MGlu2 receptor agonists MGlu3 receptor agonists Cyclopropanes Cyclopentanes

Mechanism of action

Effects

Clinical development

See also

References