| 词条 | Eglumegad |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 443721449 | IUPAC_name = (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid | image = Eglumegad.svg | width = 180 | tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 176199-48-7 | ATC_prefix = none | ATC_suffix = | PubChem = 213056 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 184747 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = VTAARTQTOOYTES-RGDLXGNYSA-N | IUPHAR_ligand = 1393 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | UNII_Ref = {{fdacite|correct|FDA}} | UNII = ONU5A67T2S | C=8 | H=11 | N=1 | O=4 | molecular_weight = 185.18 g/mol | smiles = O=C(O)[C@H]1[C@]2([H])CC[C@](C(O)=O)(N)[C@@]21[H] }}Eglumegad (LY354740) 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 actionEglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).[4][5] It is unclear whether eglumegad directly interacts with dopamine D2 receptors.[6][7] EffectsIn 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.[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] Eglumegad 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. Eglumegad 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 eglumegad 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 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[19] which is generally a better model for schizophrenia than the 5HT2A agonist hallucinogens.[20] Eglumegad 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 eglumegad resulted in a marked diminution of yohimbine-induced stress response in those animals.[21] In human adrenocortical cells, eglumegad has been shown to down-regulate intracellular cyclic AMP (cAMP) and steroidogenesis, with a significant decrease in aldosterone and cortisol production.[22] Clinical developmentDevelopment 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] {{Clear}}See also
References1. ^{{cite journal | author = Pilc A | title = LY-354740 (Eli Lilly) | journal = IDrugs | volume = 6 | issue = 1 | pages = 66–71 |date=January 2003 | pmid = 12789623 | doi = }} {{Metabotropic glutamate receptor modulators}}2. ^{{cite journal |vauthors=Kłodzińska A, Chojnacka-Wójcik E, Pałucha A, Brański P, Popik P, Pilc A | title = Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models | journal = Neuropharmacology | volume = 38 | issue = 12 | pages = 1831–9 |date=December 1999 | pmid = 10608278 | doi =10.1016/S0028-3908(99)00066-0 }} 3. ^{{cite journal |vauthors=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 | title = 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 | journal = J. Med. Chem. | volume = 40 | issue = 4 | pages = 528–37 |date=February 1997 | pmid = 9046344 | doi = 10.1021/jm9606756 }} 4. ^{{cite journal |vauthors=Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S, Cockerman SL, Burnett JP, Belegaje R, Bleakman D, Monn JA | title = LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors | journal = Neuropharmacology | volume = 36 | issue = 1 | pages = 1–11 |date=January 1997 | pmid = 9144636 | doi =10.1016/S0028-3908(96)00160-8 }} 5. ^{{cite journal |vauthors=Bond A, Monn JA, Lodge D | title = A novel orally active group 2 metabotropic glutamate receptor agonist: LY354740 | journal = NeuroReport | volume = 8 | issue = 6 | pages = 1463–6 |date=April 1997 | pmid = 9172154 | doi =10.1097/00001756-199704140-00027 }} 6. ^{{cite journal |vauthors=Seeman P, Caruso C, Lasaga M | title = Dopamine partial agonist actions of the glutamate receptor agonists LY 354,740 and LY 379,268 | journal = Synapse | volume = 62 | issue = 2 | pages = 154–8 |date=February 2008 | pmid = 18000815 | doi = 10.1002/syn.20482 }} 7. ^{{cite journal |vauthors=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 | title = 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) | journal = J. Pharmacol. Exp. Ther. | volume = 331 | issue = 3 | pages = 1126–36 |date=December 2009 | pmid = 19755662 | doi = 10.1124/jpet.109.160598 }} 8. ^{{cite journal |vauthors=Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ | title = Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors | journal = J. Pharmacol. Exp. Ther. | volume = 284 | issue = 2 | pages = 651–60 |date=February 1998 | pmid = 9454811 | doi = }} 9. ^{{cite journal |vauthors=Grillon C, Cordova J, Levine LR, Morgan CA | title = Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans | journal = Psychopharmacology | volume = 168 | issue = 4 | pages = 446–54 |date=August 2003 | pmid = 12709777 | doi = 10.1007/s00213-003-1444-8 }} 10. ^{{cite journal |vauthors=Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ | title = LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress | journal = Stress | volume = 6 | issue = 3 | pages = 189–97 |date=September 2003 | pmid = 13129812 | doi = 10.1080/1025389031000146773 }} 11. ^{{cite journal |vauthors=Spinelli S, Ballard T, Gatti-McArthur S, Richards GJ, Kapps M, Woltering T, Wichmann J, Stadler H, Feldon J, Pryce CR | title = Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys | journal = Psychopharmacology | volume = 179 | issue = 1 | pages = 292–302 |date=April 2005 | pmid = 15678362 | doi = 10.1007/s00213-004-2126-x }} 12. ^{{cite journal |vauthors=Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ | title = LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats | journal = Neuropharmacology | volume = 36 | issue = 11–12 | pages = 1511–6 | year = 1997 | pmid = 9517421 | doi =10.1016/S0028-3908(97)00170-6 }} 13. ^{{cite journal |vauthors=Vandergriff J, Rasmussen K | title = The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal | journal = Neuropharmacology | volume = 38 | issue = 2 | pages = 217–22 |date=February 1999 | pmid = 10218862 | doi =10.1016/S0028-3908(98)00196-8 }} 14. ^{{cite journal |vauthors=Popik P, Kozela E, Pilc A | title = Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice | journal = Br. J. Pharmacol. | volume = 130 | issue = 6 | pages = 1425–31 |date=July 2000 | pmid = 10903986 | pmc = 1572198 | doi = 10.1038/sj.bjp.0703438 }} 15. ^{{cite journal |vauthors=Kingston AE, O'Neill MJ, Lam A, Bales KR, Monn JA, Schoepp DD | title = Neuroprotection by metabotropic glutamate receptor glutamate receptor agonists: LY354740, LY379268 and LY389795 | journal = Eur. J. Pharmacol. | volume = 377 | issue = 2–3 | pages = 155–65 |date=July 1999 | pmid = 10456425 | doi =10.1016/S0014-2999(99)00397-0 }} 16. ^{{cite journal |vauthors=Allen JW, Ivanova SA, Fan L, Espey MG, Basile AS, Faden AI | title = Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury | journal = J. Pharmacol. Exp. Ther. | volume = 290 | issue = 1 | pages = 112–20 |date=July 1999 | pmid = 10381766 | doi = }} 17. ^{{cite journal |vauthors=Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK | title = Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex | journal = J. Pharmacol. Exp. Ther. | volume = 292 | issue = 1 | pages = 76–87 |date=January 2000 | pmid = 10604933 | doi = }} 18. ^{{cite journal |vauthors=Gewirtz JC, Marek GJ | title = Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors | journal = Neuropsychopharmacology | volume = 23 | issue = 5 | pages = 569–76 |date=November 2000 | pmid = 11027922 | doi = 10.1016/S0893-133X(00)00136-6 }} 19. ^{{cite journal |vauthors=Schreiber R, Lowe D, Voerste A, De Vry J | title = LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine | journal = Eur. J. Pharmacol. | volume = 388 | issue = 2 | pages = R3–4 |date=January 2000 | pmid = 10666513 | doi =10.1016/S0014-2999(99)00844-4 }} 20. ^{{cite journal |vauthors=DD DD, Marek GJ | title = Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? | journal = Curr Drug Targets CNS Neurol Disord | volume = 1 | issue = 2 | pages = 215–25 |date=April 2002 | pmid = 12769628 | doi =10.2174/1568007024606177 }} 21. ^{{cite journal |vauthors=Coplan JD, Mathew SJ, Smith EL, Trost RC, Scharf BA, Martinez J, Gorman JM, Monn JA, Schoepp DD, Rosenblum LA | title = Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function | journal = CNS Spectr | volume = 6 | issue = 7 | pages = 607–12, 617 |date=July 2001 | pmid = 15573025 | doi = }} 22. ^{{cite journal | vauthors = ((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 | title = Glutamate Receptors and the Regulation of Steroidogenesis in the Human Adrenal Gland: The Metabotropic Pathway | journal = Molecular and Cellular Endocrinology | volume = 382| issue = 1| pages = 170–7|date=January 2014 | doi = 10.1016/j.mce.2013.09.025 | pmid = 24080311}} 23. ^{{cite journal |vauthors=Bergink V, Westenberg HG | title = Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740 | journal = Int Clin Psychopharmacol | volume = 20 | issue = 6 | pages = 291–3 |date=November 2005 | pmid = 16192835 | doi =10.1097/00004850-200511000-00001 }} 24. ^{{cite journal |vauthors=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 | title = 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 | journal = J. Med. Chem. | volume = 48 | issue = 16 | pages = 5305–20 |date=August 2005 | pmid = 16078848 | doi = 10.1021/jm050235r }} 25. ^{{cite journal |vauthors=Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, McKinzie DL | title = Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344 | journal = J. Pharmacol. Exp. Ther. | volume = 316 | issue = 2 | pages = 905–13 |date=February 2006 | pmid = 16223873 | doi = 10.1124/jpet.105.091926 }} 26. ^{{cite journal | author = Danysz W | title = LY-544344. Eli Lilly | journal = IDrugs | volume = 8 | issue = 9 | pages = 755–62 |date=September 2005 | pmid = 16118698 | doi = }} 27. ^{{cite journal |vauthors=Perkins EJ, Abraham T | title = 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 | journal = Drug Metab. Dispos. | volume = 35 | issue = 10 | pages = 1903–9 |date=October 2007 | pmid = 17646281 | doi = 10.1124/dmd.107.016154 }} 28. ^{{cite journal |vauthors=Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD | title = Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder | journal = Neuropsychopharmacology | volume = 33 | issue = 7 | pages = 1603–10 |date=June 2008 | pmid = 17712352 | doi = 10.1038/sj.npp.1301531 }} 7 : Anxiolytics|Amino acids|Eli Lilly and Company|MGlu2 receptor agonists|MGlu3 receptor agonists|Cyclopropanes|Cyclopentanes |
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