L-687,414

L-687,414
Clinical data
Other namesL-687414; L687414; cis-4-Methyl-HA-966
Drug classGlycine-site NMDA receptor antagonist or very weak partial agonist
Identifiers
  • (3S,4S)-3-amino-1-hydroxy-4-methylpyrrolidin-2-one
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC5H10N2O2
Molar mass130.147 g·mol−1
3D model (JSmol)
  • C[C@H]1CN(C(=O)[C@H]1N)O
  • InChI=1S/C5H10N2O2/c1-3-2-7(9)5(8)4(3)6/h3-4,9H,2,6H2,1H3/t3-,4-/m0/s1
  • Key:SKYSFPFYQBZGDC-IMJSIDKUSA-N

L-687,414 is a glycine-site NMDA receptor antagonist or low-efficacy partial agonist (EmaxTooltip maximal efficacy ≈ 10%) which is used in scientific research.[1][2][3][4][5] It a close analogue of HA-966.[5] The drug has been found to produce hyperlocomotion (a psychostimulant-like effect),[6][7] analgesia[4] or antinociceptive effects,[8][9] anticonvulsant effects,[2][6] and neuroprotective effects in animals.[10] In contrast to uncompetitive NMDA receptor antagonists like ketamine and phencyclidine (PCP), L-687,414 has not been associated with the development of brain vacuoles (i.e., Olney's lesions) in animals.[11]

Trace amine-associated receptor 1 (TAAR1) partial and full agonists, including RO5166017, RO5203648, RO5256390, and RO5263397, have been found to reverse the hyperlocomotion induced by L-687,414 as well as by other NMDA receptor antagonists like PCP in rodents.[12][13][14][15][16] Similarly, glycine transporter 1 (GlyT1) inhibitors reverse the hyperlocomotion induced by L-687,414 in rodents.[17][7][18][19] As such, TAAR1 agonists and GlyT1 inhibitors may have antipsychotic-like properties.[12][17]

References

  1. ^ Monaghan, Daniel T.; Jane, David E. (2009). "Pharmacology of NMDA Receptors". CRC Press/Taylor & Francis. PMID 21204415. Retrieved 9 January 2025.
  2. ^ a b Smith SE, Meldrum BS (January 1992). "The glycine-site NMDA receptor antagonist, R-(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one, L-687,414 is anticonvulsant in baboons". Eur J Pharmacol. 211 (1): 109–111. doi:10.1016/0014-2999(92)90270-e. PMID 1535595.
  3. ^ Grimwood S, Wilde GJ, Foster AC (May 1993). "Interactions between the glutamate and glycine recognition sites of the N-methyl-D-aspartate receptor from rat brain, as revealed from radioligand binding studies". J Neurochem. 60 (5): 1729–1738. doi:10.1111/j.1471-4159.1993.tb13397.x. PMID 8097236.
  4. ^ a b Laird JM, Mason GS, Webb J, Hill RG, Hargreaves RJ (April 1996). "Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation-induced mechanical hyperalgesia in rats". Br J Pharmacol. 117 (7): 1487–1492. doi:10.1111/j.1476-5381.1996.tb15311.x. PMC 1909461. PMID 8730744.
  5. ^ a b Priestley T, Marshall GR, Hill RG, Kemp JA (August 1998). "L-687,414, a low efficacy NMDA receptor glycine site partial agonist in vitro, does not prevent hippocampal LTP in vivo at plasma levels known to be neuroprotective". Br J Pharmacol. 124 (8): 1767–1773. doi:10.1038/sj.bjp.0702010. PMC 1565569. PMID 9756395.
  6. ^ a b Tricklebank MD, Bristow LJ, Hutson PH, Leeson PD, Rowley M, Saywell K, Singh L, Tattersall FD, Thorn L, Williams BJ (November 1994). "The anticonvulsant and behavioural profile of L-687,414, a partial agonist acting at the glycine modulatory site on the N-methyl-D-aspartate (NMDA) receptor complex". Br J Pharmacol. 113 (3): 729–736. doi:10.1111/j.1476-5381.1994.tb17054.x. PMC 1510413. PMID 7858861.
  7. ^ a b Alberati D, Moreau JL, Mory R, Pinard E, Wettstein JG (December 2010). "Pharmacological evaluation of a novel assay for detecting glycine transporter 1 inhibitors and their antipsychotic potential". Pharmacol Biochem Behav. 97 (2): 185–191. doi:10.1016/j.pbb.2010.07.016. PMID 20678516.
  8. ^ Millan MJ, Seguin L (August 1994). "Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice". Neurosci Lett. 178 (1): 139–143. doi:10.1016/0304-3940(94)90309-3. PMID 7816323.
  9. ^ Boyce S, Wyatt A, Webb JK, O'Donnell R, Mason G, Rigby M, Sirinathsinghji D, Hill RG, Rupniak NM (May 1999). "Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn". Neuropharmacology. 38 (5): 611–623. doi:10.1016/s0028-3908(98)00218-4. PMID 10340299.
  10. ^ Gill R, Hargreaves RJ, Kemp JA (March 1995). "The neuroprotective effect of the glycine site antagonist 3R-(+)-cis-4-methyl-HA966 (L-687,414) in a rat model of focal ischaemia". J Cereb Blood Flow Metab. 15 (2): 197–204. doi:10.1038/jcbfm.1995.25. PMID 7860653.
  11. ^ Hargreaves RJ, Hill RG, Iversen LL (1994). "Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology". Acta Neurochir Suppl (Wien). 60: 15–19. doi:10.1007/978-3-7091-9334-1_4. PMID 7976530.
  12. ^ a b Liu J, Wu R, Li JX (January 2024). "TAAR1 as an emerging target for the treatment of psychiatric disorders". Pharmacol Ther. 253: 108580. doi:10.1016/j.pharmthera.2023.108580. PMID 38142862.
  13. ^ Wu R, Li JX (December 2021). "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs. 35 (12): 1239–1248. doi:10.1007/s40263-021-00871-4. PMC 8787759. PMID 34766253.
  14. ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A. 108 (20): 8485–8490. Bibcode:2011PNAS..108.8485R. doi:10.1073/pnas.1103029108. PMC 3101002. PMID 21525407.
  15. ^ Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, Morairty SR, Harmeier A, Groebke Zbinden K, Norcross RD, Bradaia A, Kilduff TS, Biemans B, Pouzet B, Caron MG, Canales JJ, Wallace TL, Wettstein JG, Hoener MC (December 2012). "Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics". Biol Psychiatry. 72 (11): 934–942. doi:10.1016/j.biopsych.2012.05.014. PMID 22705041.
  16. ^ Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC (May 2013). "A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight". Mol Psychiatry. 18 (5): 543–556. doi:10.1038/mp.2012.57. PMID 22641180.
  17. ^ a b Hashimoto K (2011). "Glycine transporter-1: a new potential therapeutic target for schizophrenia". Curr Pharm Des. 17 (2): 112–120. doi:10.2174/138161211795049598. PMID 21355838.
  18. ^ Alberati D, Moreau JL, Lengyel J, Hauser N, Mory R, Borroni E, Pinard E, Knoflach F, Schlotterbeck G, Hainzl D, Wettstein JG (February 2012). "Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia". Neuropharmacology. 62 (2): 1152–1161. doi:10.1016/j.neuropharm.2011.11.008. PMID 22138164.
  19. ^ Amberg W, Lange UE, Ochse M, Pohlki F, Behl B, Relo AL, Hornberger W, Hoft C, Mezler M, Sydor J, Wang Y, Zhao H, Brewer JT, Dietrich J, Li H, Akritopoulou-Zanze I, Lao Y, Hannick SM, Ku YY, Vasudevan A (September 2018). "Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors". J Med Chem. 61 (17): 7503–7524. doi:10.1021/acs.jmedchem.8b00300. PMID 30080045.


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