LY-341495

Last updated
LY-341495
LY-341,495.svg
Clinical data
Other names(2S)-2-Amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid
Identifiers
  • 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
CAS Number
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C20H19NO5
Molar mass 353.374 g·mol−1
3D model (JSmol)
  • C1[C@@H]([C@H]1[C@@](CC2C3=CC=CC=C3OC4=CC=CC=C24)(C(=O)O)N)C(=O)O
  • InChI=1S/C20H19NO5/c21-20(19(24)25,15-9-13(15)18(22)23)10-14-11-5-1-3-7-16(11)26-17-8-4-2-6-12(14)17/h1-8,13-15H,9-10,21H2,(H,22,23)(H,24,25)/t13-,15-,20-/m0/s1 X mark.svgN
  • Key:VLZBRVJVCCNPRJ-KPHUOKFYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

LY-341495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors (mGluR2/3). [1] [2] [3] [4]

It is used in scientific research in several different areas, showing antidepressant effects in animal models, [5] [6] [7] [8] increasing the behavioural effects of hallucinogenic drugs in animal tests, [9] [10] [11] [12] and increasing the analgesic effects of μ-opioid agonists, [13] [14] as well as modulating dopamine receptor function. [15] [16] [17]

The 1-fluorocyclopropane analog has a superior pharmacokinetic profile and similar mGluR2/3 affinity, and making a prodrug from this with the heptyl ester increases bioavailability still further. [18]

1-fluoro-LY-341,495 heptyl ester LY-341,495 prodrug.svg
1-fluoro-LY-341,495 heptyl ester

See also

Related Research Articles

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References

  1. ↑ Ornstein PL, Bleisch TJ, Arnold MB, Kennedy JH, Wright RA, Johnson BG, Tizzano JP, Helton DR, Kallman MJ, Schoepp DD, Hérin M (January 1998). "2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability". Journal of Medicinal Chemistry. 41 (3): 358–78. doi:10.1021/jm970498o. PMID   9464367.
  2. ↑ Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD (1998). "LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors". Neuropharmacology. 37 (1): 1–12. doi:10.1016/s0028-3908(97)00191-3. PMID   9680254. S2CID   27186381.
  3. ↑ Fitzjohn SM, Bortolotto ZA, Palmer MJ, Doherty AJ, Ornstein PL, Schoepp DD, Kingston AE, Lodge D, Collingridge GL (December 1998). "The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity". Neuropharmacology. 37 (12): 1445–58. doi:10.1016/s0028-3908(98)00145-2. PMID   9886667. S2CID   26102806.
  4. ↑ Johnson BG, Wright RA, Arnold MB, Wheeler WJ, Ornstein PL, Schoepp DD (October 1999). "[3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells". Neuropharmacology. 38 (10): 1519–29. doi:10.1016/s0028-3908(99)00053-2. PMID   10530814. S2CID   36767061.
  5. ↑ Pilc A, Chaki S, Nowak G, Witkin JM (March 2008). "Mood disorders: regulation by metabotropic glutamate receptors". Biochemical Pharmacology. 75 (5): 997–1006. doi:10.1016/j.bcp.2007.09.021. PMID   18164691.
  6. ↑ Matrisciano F, Panaccione I, Zusso M, Giusti P, Tatarelli R, Iacovelli L, Mathé AA, Gruber SH, Nicoletti F, Girardi P (August 2007). "Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication?". Molecular Psychiatry. 12 (8): 704–6. doi:10.1038/sj.mp.4002005. PMID   17653204. S2CID   7906551.
  7. ↑ Koike H, Chaki S (September 2014). "Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats". Behavioural Brain Research. 271: 111–5. doi:10.1016/j.bbr.2014.05.065. PMID   24909673. S2CID   19982406.
  8. ↑ Lepack AE, Bang E, Lee B, Dwyer JM, Duman RS (December 2016). "Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures". Neuropharmacology. 111: 242–252. doi:10.1016/j.neuropharm.2016.09.011. PMC   5075989 . PMID   27634096.
  9. ↑ 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.
  10. ↑ Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E (August 2007). "A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis". Molecular Pharmacology. 72 (2): 477–84. doi:10.1124/mol.107.035170. PMID   17526600. S2CID   3097502.
  11. ↑ Carbonaro TM, Eshleman AJ, Forster MJ, Cheng K, Rice KC, Gatch MB (January 2015). "The role of 5-HT2A, 5-HT 2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice". Psychopharmacology. 232 (1): 275–84. doi:10.1007/s00213-014-3658-3. PMC   4282596 . PMID   24985890.
  12. ↑ Moreno JL, González-Maeso J (2018). "Crosstalk Between 5-HT2A and mGlu2 Receptors: Implications in Schizophrenia and Its Treatment". 5-HT2A Receptors in the Central Nervous System. The Receptors. Vol. 32. pp. 147–189. doi:10.1007/978-3-319-70474-6_7. ISBN   978-3-319-70472-2.
  13. ↑ Fischer BD, Miller LL, Henry FE, Picker MJ, Dykstra LA (June 2008). "Increased efficacy of micro-opioid agonist-induced antinociception by metabotropic glutamate receptor antagonists in C57BL/6 mice: comparison with (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959)". Psychopharmacology. 198 (2): 271–8. doi:10.1007/s00213-008-1130-y. PMID   18392754. S2CID   24658889.
  14. ↑ Fischer BD, Zimmerman EI, Picker MJ, Dykstra LA (February 2008). "Morphine in combination with metabotropic glutamate receptor antagonists on schedule-controlled responding and thermal nociception". The Journal of Pharmacology and Experimental Therapeutics. 324 (2): 732–9. doi:10.1124/jpet.107.131417. PMID   17982001. S2CID   12497552.
  15. ↑ O'Neill MF, Heron-Maxwell C, Conway MW, Monn JA, Ornstein P (October 2003). "Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice". Neuropharmacology. 45 (5): 565–74. doi:10.1016/S0028-3908(03)00232-6. PMID   12941370. S2CID   22992987.
  16. ↑ Chi H, Jang JK, Kim JH, Vezina P (October 2006). "Blockade of group II metabotropic glutamate receptors in the nucleus accumbens produces hyperlocomotion in rats previously exposed to amphetamine". Neuropharmacology. 51 (5): 986–92. doi:10.1016/j.neuropharm.2006.06.008. PMID   16901517. S2CID   22562384.
  17. ↑ Yoon HS, Jang JK, Kim JH (September 2008). "Blockade of group II metabotropic glutamate receptors produces hyper-locomotion in cocaine pre-exposed rats by interactions with dopamine receptors". Neuropharmacology. 55 (4): 555–9. doi:10.1016/j.neuropharm.2008.07.012. PMID   18675831. S2CID   12164609.
  18. ↑ Sakagami K, Yasuhara A, Chaki S, Yoshikawa R, Kawakita Y, Saito A, Taguchi T, Nakazato A (April 2008). "Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist". Bioorganic & Medicinal Chemistry. 16 (8): 4359–66. doi:10.1016/j.bmc.2008.02.066. PMID   18348906.
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