LY-341495 explained

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]

See also

Notes and References

  1. Ornstein PL, Bleisch TJ, Arnold MB, Kennedy JH, Wright RA, Johnson BG, Tizzano JP, Helton DR, Kallman MJ, Schoepp DD, Hérin M . 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 . January 1998 . 9464367 . 10.1021/jm970498o .
  2. Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD . LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors . Neuropharmacology . 1998 . 37 . 1 . 1–12 . 9680254 . 10.1016/s0028-3908(97)00191-3. 27186381 .
  3. Fitzjohn SM, Bortolotto ZA, Palmer MJ, Doherty AJ, Ornstein PL, Schoepp DD, Kingston AE, Lodge D, Collingridge GL . The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity . Neuropharmacology . 37 . 12 . 1445–58 . December 1998 . 9886667 . 10.1016/s0028-3908(98)00145-2. 26102806 .
  4. Johnson BG, Wright RA, Arnold MB, Wheeler WJ, Ornstein PL, Schoepp DD . [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 . October 1999 . 10530814 . 10.1016/s0028-3908(99)00053-2. 36767061 .
  5. Pilc A, Chaki S, Nowak G, Witkin JM . Mood disorders: regulation by metabotropic glutamate receptors . Biochemical Pharmacology . 75 . 5 . 997–1006 . March 2008 . 18164691 . 10.1016/j.bcp.2007.09.021 .
  6. Matrisciano F, Panaccione I, Zusso M, Giusti P, Tatarelli R, Iacovelli L, Mathé AA, Gruber SH, Nicoletti F, Girardi P . 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 . August 2007 . 17653204 . 10.1038/sj.mp.4002005 . 7906551 .
  7. Koike H, Chaki S . 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 . September 2014 . 24909673 . 10.1016/j.bbr.2014.05.065 . 19982406 .
  8. Lepack AE, Bang E, Lee B, Dwyer JM, Duman RS . Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures . Neuropharmacology . 111 . 242–252 . December 2016 . 27634096 . 10.1016/j.neuropharm.2016.09.011 . 5075989 .
  9. Gewirtz JC, Marek GJ . Behavioral evidence for interactions between a hallucinogenic drug and group II metabotropic glutamate receptors . Neuropsychopharmacology . 23 . 5 . 569–76 . November 2000 . 11027922 . 10.1016/S0893-133X(00)00136-6 . free .
  10. Benneyworth MA, Xiang Z, Smith RL, Garcia EE, Conn PJ, Sanders-Bush E . A selective positive allosteric modulator of metabotropic glutamate receptor subtype 2 blocks a hallucinogenic drug model of psychosis . Molecular Pharmacology . 72 . 2 . 477–84 . August 2007 . 17526600 . 10.1124/mol.107.035170 . 3097502 .
  11. Carbonaro TM, Eshleman AJ, Forster MJ, Cheng K, Rice KC, Gatch MB . 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 . January 2015 . 24985890 . 10.1007/s00213-014-3658-3 . 4282596 .
  12. Book: The Receptors . 32 . 5-HT2A Receptors in the Central Nervous System . 147–189 . Moreno JL, González-Maeso J . Crosstalk Between 5-HT2A and mGlu2 Receptors: Implications in Schizophrenia and Its Treatment . 2018 . 10.1007/978-3-319-70474-6_7 . 978-3-319-70472-2 .
  13. Fischer BD, Miller LL, Henry FE, Picker MJ, Dykstra LA . 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 . June 2008 . 18392754 . 10.1007/s00213-008-1130-y . 24658889 .
  14. Fischer BD, Zimmerman EI, Picker MJ, Dykstra LA . 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 . February 2008 . 17982001 . 10.1124/jpet.107.131417 . 12497552 .
  15. O'Neill MF, Heron-Maxwell C, Conway MW, Monn JA, Ornstein P . Group II metabotropic glutamate receptor antagonists LY341495 and LY366457 increase locomotor activity in mice . Neuropharmacology . 45 . 5 . 565–74 . October 2003 . 12941370 . 10.1016/S0028-3908(03)00232-6 . 22992987 .
  16. Chi H, Jang JK, Kim JH, Vezina P . Blockade of group II metabotropic glutamate receptors in the nucleus accumbens produces hyperlocomotion in rats previously exposed to amphetamine . Neuropharmacology . 51 . 5 . 986–92 . October 2006 . 16901517 . 10.1016/j.neuropharm.2006.06.008 . 22562384 .
  17. Yoon HS, Jang JK, Kim JH . 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 . September 2008 . 18675831 . 10.1016/j.neuropharm.2008.07.012 . 12164609 .
  18. Sakagami K, Yasuhara A, Chaki S, Yoshikawa R, Kawakita Y, Saito A, Taguchi T, Nakazato A . 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 . April 2008 . 18348906 . 10.1016/j.bmc.2008.02.066 .

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