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]
Mechanism of action
[edit]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]
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]
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]
^Pilc A (January 2003). "LY-354740 (Eli Lilly)". IDrugs. 6 (1): 66–71. PMID12789623.
^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. PMID10608278. S2CID23149472.
^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. PMID9046344.
^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. PMID9144636. S2CID45878904.
^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. PMID19755662. S2CID23981819.
^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. PMID9454811.
^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. PMID10666513.
^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. PMID12769628.
^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. PMID15573025. S2CID6029856.
^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. PMID24080311. S2CID3357749.
^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. PMID16192835. S2CID29298397.
^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. PMID16078848.
^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. PMID16223873. S2CID1352829.
^Danysz W (September 2005). "LY-544344. Eli Lilly". IDrugs. 8 (9): 755–62. PMID16118698.
^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. PMID17646281. S2CID5639829.
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