Chemistry:L-687,414

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L-687,414 is a glycine-site NMDA receptor antagonist or low-efficacy partial agonist (Emax ≈ 10%) which is used in scientific research.[1][2][3][4][5] It is 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. ↑ "Pharmacology of NMDA Receptors". Biology of the NMDA Receptor. CRC Press/Taylor & Francis. 2009. ISBN 978-1-4200-4414-0. https://www.ncbi.nlm.nih.gov/books/NBK5282/. Retrieved 9 January 2025. 
  2. ↑ 2.0 2.1 "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. January 1992. doi:10.1016/0014-2999(92)90270-e. PMID 1535595. 
  3. ↑ "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. May 1993. doi:10.1111/j.1471-4159.1993.tb13397.x. PMID 8097236. 
  4. ↑ 4.0 4.1 "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. April 1996. doi:10.1111/j.1476-5381.1996.tb15311.x. PMID 8730744. 
  5. ↑ 5.0 5.1 "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. August 1998. doi:10.1038/sj.bjp.0702010. PMID 9756395. 
  6. ↑ 6.0 6.1 "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. November 1994. doi:10.1111/j.1476-5381.1994.tb17054.x. PMID 7858861. 
  7. ↑ 7.0 7.1 "Pharmacological evaluation of a novel assay for detecting glycine transporter 1 inhibitors and their antipsychotic potential". Pharmacol Biochem Behav 97 (2): 185–191. December 2010. doi:10.1016/j.pbb.2010.07.016. PMID 20678516. 
  8. ↑ "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. August 1994. doi:10.1016/0304-3940(94)90309-3. PMID 7816323. 
  9. ↑ "Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn". Neuropharmacology 38 (5): 611–623. May 1999. doi:10.1016/s0028-3908(98)00218-4. PMID 10340299. 
  10. ↑ "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. March 1995. doi:10.1038/jcbfm.1995.25. PMID 7860653. 
  11. ↑ "Neuroprotective NMDA Antagonists: The Controversy over Their Potential for Adverse Effects on Cortical Neuronal Morphology". Brain Edema IX. Acta Neurochirurgica. Supplementum. 60. 1994. pp. 15–19. doi:10.1007/978-3-7091-9334-1_4. ISBN 978-3-7091-9336-5. 
  12. ↑ 12.0 12.1 "TAAR1 as an emerging target for the treatment of psychiatric disorders". Pharmacol Ther 253. January 2024. doi:10.1016/j.pharmthera.2023.108580. PMID 38142862. 
  13. ↑ "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs 35 (12): 1239–1248. December 2021. doi:10.1007/s40263-021-00871-4. PMID 34766253. 
  14. ↑ "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A 108 (20): 8485–8490. May 2011. doi:10.1073/pnas.1103029108. PMID 21525407. Bibcode: 2011PNAS..108.8485R. 
  15. ↑ "Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics". Biol Psychiatry 72 (11): 934–942. December 2012. doi:10.1016/j.biopsych.2012.05.014. PMID 22705041. 
  16. ↑ "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. May 2013. doi:10.1038/mp.2012.57. PMID 22641180. 
  17. ↑ 17.0 17.1 "Glycine transporter-1: a new potential therapeutic target for schizophrenia". Curr Pharm Des 17 (2): 112–120. 2011. doi:10.2174/138161211795049598. PMID 21355838. 
  18. ↑ "Glycine reuptake inhibitor RG1678: a pharmacologic characterization of an investigational agent for the treatment of schizophrenia". Neuropharmacology 62 (2): 1152–1161. February 2012. doi:10.1016/j.neuropharm.2011.11.008. PMID 22138164. 
  19. ↑ "Discovery of Novel Aminotetralines and Aminochromanes as Selective and Competitive Glycine Transporter 1 (GlyT1) Inhibitors". J Med Chem 61 (17): 7503–7524. September 2018. doi:10.1021/acs.jmedchem.8b00300. PMID 30080045. 




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