SYM-2081

SYM-2081
Names
	IUPAC name (2S,4R)-2-Amino-4-methylpentanedioic acid
	Other names (2S,4R)-4-Methylglutamic acid
Identifiers
CAS Number	31137-74-3; 77842-39-8;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:228160;
ChEMBL	ChEMBL288166;
ChemSpider	86558;
IUPHAR/BPS	10821708;
PubChem CID	95883;
CompTox Dashboard (EPA)	DTXSID901300044 ;
	InChI 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;
	SMILES C[C@H](C[C@@H](C(=O)O)N)C(=O)O;
Properties
Chemical formula	C6H11NO4
Molar mass	161.157 g·mol−1
Appearance	White solid
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

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

^ "SYM 2081". R&D Systems.
^ ^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.
^ ^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.

[1] "SYM 2081". R&D Systems.

[:0-2] 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.

[:1-3] ^ ^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.

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