Eglumetad

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Eglumetad
Eglumegad.svg
Clinical data
Other namesEglumegad; LY354740
ATC code
  • none
Identifiers
  • (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
Formula C8H11NO4
Molar mass 185.179 g·mol−1
3D model (JSmol)
  • O=C(O)[C@H]1[C@]2([H])CC[C@](C(O)=O)(N)[C@@]21[H]
  • 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 X mark.svgN
  • Key:VTAARTQTOOYTES-RGDLXGNYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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]

Contents

Mechanism of action

Eglumetad in a mGlu2 receptor bound conformation Eglumegad 3D.png
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 eglumetad 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 (talaglumetad) 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 LY544344 structure.png
LY-544,344

See also

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References

  1. ↑ Pilc A (January 2003). "LY-354740 (Eli Lilly)". IDrugs. 6 (1): 66–71. PMID   12789623.
  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.
  5. ↑ Bond A, Monn JA, Lodge D (April 1997). "A novel orally active group 2 metabotropic glutamate receptor agonist: LY354740". NeuroReport. 8 (6): 1463–6. doi:10.1097/00001756-199704140-00027. PMID   9172154. S2CID   36222393.
  6. ↑ Seeman P, Caruso C, Lasaga M (February 2008). "Dopamine partial agonist actions of the glutamate receptor agonists LY 354,740 and LY 379,268". Synapse. 62 (2): 154–8. doi:10.1002/syn.20482. hdl: 11336/108389 . PMID   18000815. S2CID   6958836.
  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.
  8. ↑ Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ (February 1998). "Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors". J. Pharmacol. Exp. Ther. 284 (2): 651–60. PMID   9454811.
  9. ↑ Grillon C, Cordova J, Levine LR, Morgan CA (August 2003). "Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans". Psychopharmacology. 168 (4): 446–54. doi:10.1007/s00213-003-1444-8. PMID   12709777. S2CID   32290461.
  10. ↑ Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ (September 2003). "LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress". Stress. 6 (3): 189–97. doi: 10.1080/1025389031000146773 . PMID   13129812. S2CID   23974589.
  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.
  12. ↑ Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ (1997). "LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats". Neuropharmacology. 36 (11–12): 1511–6. doi:10.1016/S0028-3908(97)00170-6. PMID   9517421. S2CID   37252442.
  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.
  15. ↑ Kingston AE, O'Neill MJ, Lam A, Bales KR, Monn JA, Schoepp DD (July 1999). "Neuroprotection by metabotropic glutamate receptor glutamate receptor agonists: LY354740, LY379268 and LY389795". Eur. J. Pharmacol. 377 (2–3): 155–65. doi:10.1016/S0014-2999(99)00397-0. PMID   10456425.
  16. ↑ Allen JW, Ivanova SA, Fan L, Espey MG, Basile AS, Faden AI (July 1999). "Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury". J. Pharmacol. Exp. Ther. 290 (1): 112–20. PMID   10381766.
  17. ↑ Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK (January 2000). "Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex". J. Pharmacol. Exp. Ther. 292 (1): 76–87. PMID   10604933.
  18. ↑ Gewirtz JC, Marek GJ (November 2000). "Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors". Neuropsychopharmacology. 23 (5): 569–76. doi: 10.1016/S0893-133X(00)00136-6 . PMID   11027922.
  19. ↑ Schreiber R, Lowe D, Voerste A, De Vry J (January 2000). "LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine". Eur. J. Pharmacol. 388 (2): R3–4. doi:10.1016/S0014-2999(99)00844-4. PMID   10666513.
  20. ↑ DD DD, Marek GJ (April 2002). "Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia?". Curr Drug Targets CNS Neurol Disord. 1 (2): 215–25. doi:10.2174/1568007024606177. PMID   12769628.
  21. ↑ Coplan JD, Mathew SJ, Smith EL, Trost RC, Scharf BA, Martinez J, Gorman JM, Monn JA, Schoepp DD, Rosenblum LA (July 2001). "Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function". CNS Spectr. 6 (7): 607–12, 617. doi:10.1017/S1092852900002157. PMID   15573025. S2CID   6029856.
  22. ↑ Felizola SJA, Nakamura Y, Satoh F, Morimoto R, Kikuchi K, Nakamura T, Hozawa A, Wang L, Onodera Y, Ise K, McNamara KM, Midorikawa S, Suzuki S, Sasano H (January 2014). "Glutamate Receptors and the Regulation of Steroidogenesis in the Human Adrenal Gland: The Metabotropic Pathway". Molecular and Cellular Endocrinology. 382 (1): 170–7. doi:10.1016/j.mce.2013.09.025. PMID   24080311. S2CID   3357749.
  23. ↑ Bergink V, Westenberg HG (November 2005). "Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740". Int Clin Psychopharmacol. 20 (6): 291–3. doi:10.1097/00004850-200511000-00001. PMID   16192835. S2CID   29298397.
  24. ↑ Bueno AB, Collado I, de Dios A, Domínguez C, Martín JA, Martín LM, Martínez-Grau MA, Montero C, Pedregal C, Catlow J, Coffey DS, Clay MP, Dantzig AH, Lindstrom T, Monn JA, Jiang H, Schoepp DD, Stratford RE, Tabas LB, Tizzano JP, Wright RA, Herin MF (August 2005). "Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist". J. Med. Chem. 48 (16): 5305–20. doi:10.1021/jm050235r. PMID   16078848.
  25. ↑ Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, McKinzie DL (February 2006). "Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344". J. Pharmacol. Exp. Ther. 316 (2): 905–13. doi:10.1124/jpet.105.091926. PMID   16223873. S2CID   1352829.
  26. ↑ Danysz W (September 2005). "LY-544344. Eli Lilly". IDrugs. 8 (9): 755–62. PMID   16118698.
  27. ↑ Perkins EJ, Abraham T (October 2007). "Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in rats and dogs: assessment of first-pass bioactivation and dose linearity". Drug Metab. Dispos. 35 (10): 1903–9. doi:10.1124/dmd.107.016154. PMID   17646281. S2CID   5639829.
  28. ↑ Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD (June 2008). "Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder". Neuropsychopharmacology. 33 (7): 1603–10. doi: 10.1038/sj.npp.1301531 . PMID   17712352.
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