SYM-2081
SYM2081.svg
Names
IUPAC name
(2S,4R)-2-Amino-4-methylpentanedioic acid
Other names
(2S,4R)-4-Methylglutamic acid
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
  • InChI=1S/C6H11NO4/c1-3(5(8)9)2-4(7)6(10)11/h3-4H,2,7H2,1H3,(H,8,9)(H,10,11)/t3-,4+/m1/s1
    Key: KRKRAOXTGDJWNI-DMTCNVIQSA-N
  • C[C@H](C[C@@H](C(=O)O)N)C(=O)O
Properties
C6H11NO4
Molar mass 161.157 g·mol−1
Appearance White solid[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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.[2] Given its potency and selectivity, it is a useful ligand for studying the role of kainate receptors in the central nervous system.[3]

Synthesis

SYM-2081 can be prepared through diastereomeric mixture via enzymatic synthesis, but the yield of this reaction is small.[4] 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.[4] The resulting product was mixed with excess iodomethane which yielded 4-methylated products and some unreacted starting material.[4] The trans product was purified through column chromatography.[4] Next, the product was crystallized by hexanes.[4] Tetrabutylammonium fluoride was used for its primary alcohol to selectively remove the tert-butyldiphenylsilyl (TBDPS) protecting group.[4] The Sharpless procedure was used to oxidize the alcohol.[4] This intermediate was hydrolyzed with lithium hydroxide in aqueous THF.[4] Finally, the compound was treated with trifluoroacetic acid (TFA) in dichloromethane to produce (2S,4R)-4-methylglutamic acid.[4]

Research

Some research has indicated that having the methyl group in SYM-2081 is essential for its potency.[3] SYM-2081 was 20 times more potent than its (2R,4R) isomer and 1000 times more potent than its (2S,4S) isomer.[3]

References

  1. ^ Safety Data Sheet, Tocris
  2. ^ "SYM 2081". R&D Systems.((cite web)): CS1 maint: url-status (link)
  3. ^ 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.
  4. ^ 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.((cite journal)): CS1 maint: url-status (link)