SYM-2081 is a highly selective agonist for the kainate receptor. This potent agonist has nearly 3,000 fold- and 200-fold selectivity for kainate receptors over AMPA and NMDA receptors, respectively.[1] Given its potency and selectivity, it is a useful ligand for studying the role of kainate receptors in the central nervous system.[2]

Synthesis

SYM-2081 can be prepared through diastereomeric mixture via enzymatic synthesis, but the yield of this reaction is small.[3] SYM-2081 can be produced at a multi-gram scale by starting with (S)-1-t-butoxycarbonyl-5-t-butyldiphenylsilyoxymethylpyrrolidine-2-one and treating it with one equivalent of lithium bis(trimethylsilyl)amide in tetrahydrofuran (THF) at -78 °C.[3] The resulting product was mixed with excess iodomethane which yielded 4-methylated products and some unreacted starting material.[3] The trans product was purified through column chromatography.[3] Next, the product was crystallized by hexanes.[3] Tetrabutylammonium fluoride was used for its primary alcohol to selectively remove the tert-butyldiphenylsilyl (TBDPS) protecting group.[3] The Sharpless procedure was used to oxidize the alcohol.[3] This intermediate was hydrolyzed with lithium hydroxide in aqueous THF.[3] Finally, the compound was treated with trifluoroacetic acid (TFA) in dichloromethane to produce (2S,4R)-4-methylglutamic acid.[3]

Research

Some research has indicated that having the methyl group in SYM-2081 is essential for its potency.[2] SYM-2081 was 20 times more potent than its (2R,4R) isomer and 1000 times more potent than its (2S,4S) isomer.[2]

References

  1. ^ "SYM 2081". R&D Systems.
  2. ^ a b c Donevan, S. D.; Beg, A.; Gunther, J. M.; Twyman, R. E. (May 1998). "The methylglutamate, SYM 2081, is a potent and highly selective agonist at kainate receptors". The Journal of Pharmacology and Experimental Therapeutics. 285 (2): 539–545. ISSN 0022-3565. PMID 9580595.
  3. ^ a b c d e f g h i Zi-Qiang Gu; Xiao-Fa Lin; Hesson, David P. (1995). "Diastereoselective synthesis of (2S,4R)-4-Methylglutamic acid (sym 2081): A high affinity and selective ligand at the kainate subtype of glutamate receptors". Bioorganic & Medicinal Chemistry Letters. 5 (17): 1973–1976. doi:10.1016/0960-894x(95)00335-q. Retrieved 2021-12-10.