Eglumegad

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IUPAC_name = (1S,2S,5R,6S)-2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid


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CAS_number = 176199-48-7
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PubChem = 213056
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C=8|H=11|N=1|O=4
molecular_weight = 185.18 g/mol
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Eglumegad (LY-354,740) is a research drug developed by Eli Lilly, which is being investigated for its potential in the treatment of anxiety [Pilc A. LY-354740 (Eli Lilly). "IDrugs". 2003 Jan;6(1):66-71.] and drug addiction. [Kłodzińska A, Chojnacka-Wójcik E, Pałucha A, Brański P, Popik P, Pilc A. Potential anti-anxiety, anti-addictive effects of LY 354740, a selective group II glutamate metabotropic receptors agonist in animal models. "Neuropharmacology". 1999 Dec;38(12):1831-9.] It is a glutamate derived compound and its mode of action implies a novel mechanism. [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. 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 of Medicinal Chemistry". 1997 Feb 14;40(4):528-37.]

Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (mGluR_2/3). [Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mayne NG, Wu S, Cockerman SL, Burnett JP, Belegaje R, Bleakman D, Monn JA. LY354740 is a potent and highly selective group II metabotropic glutamate receptor agonist in cells expressing human glutamate receptors. "Neuropharmacology". 1997 Jan;36(1):1-11.] [Bond A, Monn JA, Lodge D. A novel orally active group 2 metabotropic glutamate receptor agonist: LY354740. "Neuroreport". 1997 Apr 14;8(6):1463-6.] A substantial D2 dopaminergic component was also found. [PMID 18000815]

In 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. [Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ. Anxiolytic and side-effect profile of LY354740: a potent, highly selective, orally active agonist for group II metabotropic glutamate receptors. "Journal of Pharmacology and Experimental Therapeutics". 1998 Feb;284(2):651-60.] Tests in humans confirmed that it produced anxiolytic effects without producing sedation. [Grillon C, Cordova J, Levine LR, Morgan CA 3rd. Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans. "Psychopharmacology (Berlin)". 2003 Aug;168(4):446-54.] [Schoepp DD, Wright RA, Levine LR, Gaydos B, Potter WZ. LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress. "Stress". 2003 Sep;6(3):189-97.] However it did slightly reduce cognitive performance in tests on monkeys. [Spinelli S, Ballard T, Gatti-McArthur S, Richards GJ, Kapps M, Woltering T, Wichmann J, Stadler H, Feldon J, Pryce CR. Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys. "Psychopharmacology (Berlin)". 2005 Apr;179(1):292-302.]

Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both nicotine [Helton DR, Tizzano JP, Monn JA, Schoepp DD, Kallman MJ. LY354740: a metabotropic glutamate receptor agonist which ameliorates symptoms of nicotine withdrawal in rats. "Neuropharmacology". 1997 Nov-Dec;36(11-12):1511-6.] and morphine in animals, [Vandergriff J, Rasmussen K. The selective mGlu2/3 receptor agonist LY354740 attenuates morphine-withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal. "Neuropharmacology". 1999 Feb;38(2):217-22.] as well as inhibiting the development of tolerance to morphine, [Popik P, Kozela E, Pilc A. Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice. "British Journal of Pharmacology". 2000 Jul;130(6):1425-31.] raising hope that this drug may be useful for treating drug addiction in humans.

Eglumegad and related drugs are neuroprotective [Kingston AE, O'Neill MJ, Lam A, Bales KR, Monn JA, Schoepp DD. Neuroprotection by metabotropic glutamate receptor glutamate receptor agonists: LY354740, LY379268 and LY389795. "European Journal of Pharmacology". 1999 Jul 21;377(2-3):155-65.] and are synergistic with the neuroprotection produced by NMDA antagonist drugs, [Allen JW, Ivanova SA, Fan L, Espey MG, Basile AS, Faden AI. Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury. "Journal of Pharmacology and Experimental Therapeutics". 1999 Jul;290(1):112-20.] 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 5HT_2A agonist hallucinogens, [Marek GJ, Wright RA, Schoepp DD, Monn JA, Aghajanian GK. Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex. "Journal of Pharmacology and Experimental Therapeutics". 2000 Jan;292(1):76-87.] while conversely the mGluR_2/3 antagonist LY-341,495 increased the behavioural effects of these drugs. [Gewirtz JC, Marek GJ. Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors. "Neuropsychopharmacology". 2000 Nov;23(5):569-76.] This suggests that mGluR_2/3 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 [Schreiber R, Lowe D, Voerste A, De Vry J. LY354740 affects startle responding but not sensorimotor gating or discriminative effects of phencyclidine. "European Journal of Pharmacology. 2000 Jan 28;388(2):R3-4.] which is generally a better model for schizophrenia than the 5HT_2A agonist hallucinogens. [DD DD, Marek GJ. Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia? "Current Drug Targets. CNS and Neurological Disorders". 2002 Apr;1(2):215-25.]

Development of this drug is continuing, with several clinical trials completed and more planned. [Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD. Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder. "Neuropsychopharmacology". 2007 Aug 22.] Poor oral bioavailability of the original formulation led to limited efficacy in the initial human trials, [Bergink V, Westenberg HG. Metabotropic glutamate II receptor agonists in panic disorder: a double blind clinical trial with LY354740. "International Clinical Psychopharmacology". 2005 Nov;20(6):291-3.] and so the prodrug form LY-544,344 looks more likely to be the final canditate for aspired marketing. [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. 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 of Medicinal Chemistry". 2005 Aug 11;48(16):5305-20.] [Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, McKinzie DL. Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344. "Journal of Pharmacology and Experimental Therapeutics". 2006 Feb;316(2):905-13.] [Danysz W. LY-544344. Eli Lilly. "IDrugs". 2005 Sep;8(9):755-62.]

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