Eglumetad

Eglumetad (INN; also known as eglumegad) is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety[1] and drug addiction.[2] It is a glutamate derived compound and its mode of action implies a novel mechanism.[3]

Eglumetad
Clinical data
Other namesEglumegad; LY354740
ATC code
  • none
Identifiers
IUPAC name
  • (1S,2S,5R,6S)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC8H11NO4
Molar mass185.179 g·mol−1
3D model (JSmol)
SMILES
  • O=C(O)[C@H]1[C@]2([H])CC[C@](C(O)=O)(N)[C@@]21[H]
InChI
  • InChI=1S/C8H11NO4/c9-8(7(12)13)2-1-3-4(5(3)8)6(10)11/h3-5H,1-2,9H2,(H,10,11)(H,12,13)/t3-,4-,5-,8-/m0/s1 N
  • Key:VTAARTQTOOYTES-RGDLXGNYSA-N N
 NY (what is this?)  (verify)

Mechanism of action
Eglumetad in a mGlu2 receptor bound conformation

Eglumetad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).[4][5] It is unclear whether eglumetad directly interacts with dopamine D2 receptors.[6][7]

Effects

In experiments on mice, eglumetad 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.[8] Tests in humans confirmed that it produced anxiolytic effects without producing sedation.[9][10] However it did slightly reduce cognitive performance in tests on monkeys.[11]

Eglumetad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine[12] and morphine in animals,[13] as well as inhibiting the development of tolerance to morphine,[14] raising hope that this drug may be useful for treating drug addiction in humans.

Eglumetad and related drugs are neuroprotective[15] and are synergistic with the neuroprotection produced by N-Methyl-D-aspartic acid (NMDA) antagonist drugs,[16] 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 5HT2A agonist hallucinogens,[17] while conversely the mGluR2/3 antagonist LY341495 increased the behavioural effects of these drugs.[18] This suggests that mGluR2/3 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[19] which is generally a better model for schizophrenia than the 5HT2A agonist hallucinogens.[20]

Eglumetad also interferes in the hypothalamic–pituitary–adrenal axis, with chronic oral administration of this drug leading to markedly reduced baseline cortisol levels in bonnet macaques (Macaca radiata); acute infusion of eglumetad resulted in a marked diminution of yohimbine-induced stress response in those animals.[21]

In human adrenocortical cells, eglumetad has been shown to down-regulate intracellular cyclic AMP (cAMP) and steroidogenesis, with a significant decrease in aldosterone and cortisol production.[22]

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,[23] and so the prodrug form LY544344 did seem to be a more likely drug candidate for further development.[24][25][26][27] However a clinical trial of LY544344 was discontinued early based on findings of convulsions in preclinical studies.[28]

LY-544,344

See also

References
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  2. Kłodzińska A, Chojnacka-Wójcik E, Pałucha A, Brański P, Popik P, Pilc A (December 1999). "Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models". Neuropharmacology. 38 (12): 1831–9. doi:10.1016/S0028-3908(99)00066-0. PMID 10608278. S2CID 23149472.
  3. Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD (February 1997). "Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties". J. Med. Chem. 40 (4): 528–37. doi:10.1021/jm9606756. PMID 9046344.
  4. Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S, Cockerman SL, Burnett JP, Belegaje R, Bleakman D, Monn JA (January 1997). "LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors". Neuropharmacology. 36 (1): 1–11. doi:10.1016/S0028-3908(96)00160-8. PMID 9144636. S2CID 45878904.
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  7. Fell MJ, Perry KW, Falcone JF, Johnson BG, Barth VN, Rash KS, Lucaites VL, Threlkeld PG, Monn JA, McKinzie DL, Marek GJ, Svensson KA, Nelson DL (December 2009). "In vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the metabotropic glutamate 2/3 receptor agonists 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740) and (−)-2-oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic acid (LY379268)". J. Pharmacol. Exp. Ther. 331 (3): 1126–36. doi:10.1124/jpet.109.160598. PMID 19755662. S2CID 23981819.
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  11. Spinelli S, Ballard T, Gatti-McArthur S, Richards GJ, Kapps M, Woltering T, Wichmann J, Stadler H, Feldon J, Pryce CR (April 2005). "Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys" (PDF). Psychopharmacology. 179 (1): 292–302. doi:10.1007/s00213-004-2126-x. hdl:20.500.11850/33217. PMID 15678362. S2CID 9612277.
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  13. Vandergriff J, Rasmussen K (February 1999). "The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal". Neuropharmacology. 38 (2): 217–22. doi:10.1016/S0028-3908(98)00196-8. PMID 10218862. S2CID 41921622.
  14. Popik P, Kozela E, Pilc A (July 2000). "Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice". Br. J. Pharmacol. 130 (6): 1425–31. doi:10.1038/sj.bjp.0703438. PMC 1572198. PMID 10903986.
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