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{{Short description|Chemical compound}}
{{drugbox
{{Drugbox
⚫ | verifiedrevid = 443719755
| Verifiedfields = changed
⚫ | IUPAC_name = (1S,2S,5R,6S)-2-aminobicyclohexane-2,6-dicarboxylic acid
| Watchedfields = changed
⚫ | image = Eglumegad.png
⚫ | verifiedrevid = 443721449
| width = 160
⚫ | IUPAC_name = (1''S'',2''S'',5''R'',6''S'')-2-Aminobicyclohexane-2,6-dicarboxylic acid
⚫ | CAS_number = 176199-48-7
⚫ | image = Eglumegad.svg
⚫ | ATC_prefix = none
| width = 180
⚫ | ATC_suffix =

<!--Clinical data-->
| tradename =
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<!--Identifiers-->
| 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
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| StdInChIKey = VTAARTQTOOYTES-RGDLXGNYSA-N
⚫ | IUPHAR_ligand = 1393
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| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = ONU5A67T2S | UNII = ONU5A67T2S
| synonyms = Eglumegad; LY354740
⚫ | PubChem = 213056

⚫ | IUPHAR_ligand = 1396
<!--Chemical data-->
⚫ | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = | C=8 | H=11 | N=1 | O=4
| smiles = O=C(O)12()CC(C(O)=O)(N)21
| C=8|H=11|N=1|O=4
| molecular_weight = 185.18 g/mol
⚫ | bioavailability =
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}} }}


'''Eglumegad''' ('''LY354740''') is a research drug developed by ], which is being investigated for its potential in the treatment of ]<ref>Pilc A. LY-354740 (Eli Lilly). ''IDrugs''. 2003 Jan;6(1):66-71.</ref> and drug addiction.<ref>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.</ref> It is a ] derived compound and its mode of action implies a novel mechanism.<ref>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-aminobicyclohexane-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.</ref> '''Eglumetad''' (]; also known as '''eglumegad''') is a research drug developed by ], which is being investigated for its potential in the treatment of ]<ref name="pmid12789623">{{cite journal | author = Pilc A | title = LY-354740 (Eli Lilly) | journal = IDrugs | volume = 6 | issue = 1 | pages = 66–71 |date=January 2003 | pmid = 12789623 }}</ref> and drug addiction.<ref name="pmid10608278">{{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 | s2cid = 23149472 }}</ref> It is a ] derived compound and its mode of action implies a novel mechanism.<ref name="pmid9046344">{{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-aminobicyclohexane-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 }}</ref>


==Mechanism of action== ==Mechanism of action==

Eglumegad acts as a group-selective agonist for the group II metabotropic glutamate receptors (]<sub>/</sub>]).<ref>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.</ref><ref>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.</ref> Findings about a direct interaction on ] are inconsistent.<ref>PMID 18000815</ref><ref>PMID 19755662</ref>
]

Eglumetad acts as a group-selective agonist for the group II metabotropic glutamate receptors (]<sub>/</sub>]).<ref name="pmid9144636">{{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 | s2cid = 45878904 }}</ref><ref name="pmid9172154">{{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 | s2cid = 36222393 }}</ref> It is unclear whether eglumetad directly interacts with ].<ref name="pmid18000815">{{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 | hdl = 11336/108389 | s2cid = 6958836 | hdl-access = free }}</ref><ref name="pmid19755662">{{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-aminobicyclohexane-2,6-bicaroxylate monohydrate (LY354740) and (−)-2-oxa-4-aminobicyclo 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 | s2cid = 23981819 }}</ref>


==Effects== ==Effects==
In experiments on mice, eglumegad was found to be as effective as ] 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.<ref>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.</ref> Tests in humans confirmed that it produced anxiolytic effects without producing sedation.<ref>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.</ref><ref>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.</ref> However it did slightly reduce cognitive performance in tests on monkeys.<ref>Spinelli S, Ballard T, Gatti-McArthur S, Richards GJ, Kapps M, Woltering T, Wichmann J, Stadler H, Feldon J, Pryce CR. Effects of the ]/] agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys. ''Psychopharmacology (Berlin)''. 2005 Apr;179(1):292-302.</ref> In experiments on mice, eglumetad was found to be as effective as ] 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.<ref name="pmid9454811">{{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 }}</ref> Tests in humans confirmed that it produced anxiolytic effects without producing sedation.<ref name="pmid12709777">{{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 | s2cid = 32290461 | url = https://zenodo.org/record/1232619 }}</ref><ref name="pmid13129812">{{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 | s2cid = 23974589 | doi-access = free }}</ref> However it did slightly reduce cognitive performance in tests on monkeys.<ref name="pmid15678362">{{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 | hdl = 20.500.11850/33217 | s2cid = 9612277 | url = http://doc.rero.ch/record/310361/files/213_2004_Article_2126.pdf | hdl-access = free }}</ref>

⚫ Eglumetad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both ]<ref name="pmid9517421">{{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 | s2cid = 37252442 }}</ref> and ] in animals,<ref name="pmid10218862">{{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 | s2cid = 41921622 }}</ref> as well as inhibiting the development of tolerance to morphine,<ref name="pmid10903986">{{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 }}</ref> raising hope that this drug may be useful for treating drug addiction in humans.

⚫ Eglumetad and related drugs are neuroprotective<ref name="pmid10456425">{{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 }}</ref> and are synergistic with the neuroprotection produced by ] (NMDA) antagonist drugs,<ref name="pmid10381766">{{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 }}</ref> 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 5HT<sub>2A</sub> agonist hallucinogens,<ref name="pmid10604933">{{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 }}</ref> while conversely the mGluR<sub>2/3</sub> antagonist ] increased the behavioural effects of these drugs.<ref name="pmid11027922">{{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 | doi-access = free }}</ref> This suggests that mGluR<sub>2/3</sub> 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 ]<ref name="pmid10666513">{{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 }}</ref> which is generally a better model for schizophrenia than the 5HT<sub>2A</sub> agonist hallucinogens.<ref name="pmid12769628">{{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 }}</ref>
⚫ Eglumegad has also been found to be effective in relieving the symptoms of withdrawal from chronic use of both ]<ref>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.</ref> and ] in animals,<ref>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.</ref> as well as inhibiting the development of tolerance to morphine,<ref>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.</ref> raising hope that this drug may be useful for treating drug addiction in humans.


Eglumetad also interferes in the ], with chronic oral administration of this drug leading to markedly reduced baseline ] levels in bonnet macaques (]); acute infusion of eglumetad resulted in a marked diminution of ]-induced ] in those animals.<ref name="pmid15573025">{{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 = 10.1017/S1092852900002157| s2cid = 6029856 }}</ref>
⚫ Eglumegad and related drugs are neuroprotective<ref>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.</ref> and are synergistic with the neuroprotection produced by NMDA antagonist drugs,<ref>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.</ref> which may make these drugs useful in aiding recovery from brain injury.


In human ], eglumetad has been shown to down-regulate intracellular ] (cAMP) and ], with a significant decrease in ] and cortisol production.<ref>{{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| s2cid = 3357749 }}</ref>
⚫ This class of drugs also interacts with hallucinogenic drugs, with eglumegad reducing the effects of 5HT<sub>2A</sub> agonist hallucinogens,<ref>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.</ref> while conversely the mGluR<sub>2/3</sub> antagonist ] increased the behavioural effects of these drugs.<ref>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.</ref> This suggests that mGluR<sub>2/3</sub> 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 ]<ref>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.</ref> which is generally a better model for schizophrenia than the 5HT<sub>2A</sub> agonist hallucinogens.<ref>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.</ref>


==Clinical development== ==Clinical development==
Development of this drug is continuing, with several clinical trials completed and more planned.<ref name="pmid17712352">{{cite journal |author=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 |year=2008 |month=June |pmid=17712352 |doi=10.1038/sj.npp.1301531 |url=}}</ref> Poor oral bioavailability of the original formulation led to limited efficacy in the initial human trials,<ref>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.</ref> and so the ] form LY544344 looks more likely to be the final candidate for aspired marketing.<ref>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-aminobicyclohexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. ''Journal of Medicinal Chemistry''. 2005 Aug 11;48(16):5305-20.</ref><ref>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.</ref><ref>Danysz W. LY-544344. Eli Lilly. ''IDrugs''. 2005 Sep;8(9):755-62.</ref><ref name="pmid17646281">{{cite journal |author=Perkins EJ, Abraham T |title=Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S,2S,5R,6S)-2-aminobicyclohexen-2,6-dicarboxylic acid (LY544344) in rats and dogs: assessment of first-pass bioactivation and dose linearity |journal=Drug Metabolism and Disposition: the Biological Fate of Chemicals |volume=35 |issue=10 |pages=1903–9 |year=2007 |month=October |pmid=17646281 |doi=10.1124/dmd.107.016154 |url=}}</ref> 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,<ref name="pmid16192835">{{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 | s2cid = 29298397 }}</ref> and so the ] form LY544344 (talaglumetad) did seem to be a more likely drug candidate for further development.<ref name="pmid16078848">{{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-aminobicyclohexane-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 }}</ref><ref name="pmid16223873">{{cite journal |vauthors=Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, McKinzie DL | s2cid = 1352829 | 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 }}</ref><ref name="pmid16118698">{{cite journal | author = Danysz W | title = LY-544344. Eli Lilly | journal = IDrugs | volume = 8 | issue = 9 | pages = 755–62 |date=September 2005 | pmid = 16118698 }}</ref><ref name="pmid17646281">{{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-aminobicyclohexen-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 | s2cid = 5639829 }}</ref> However a clinical trial of LY544344 was discontinued early based on findings of convulsions in preclinical studies.<ref name="pmid17712352">{{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 | doi-access = free }}</ref>


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==See also== ==See also==
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== References == ==References==
{{reflist}} {{Reflist|35em}}


{{Metabotropic glutamate receptor modulators}}
{{Glutamate_receptor_ligands}}
{{Anxiolytics}}


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