Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l -Glu or l -Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. ( S )-2-methylglutamate, or ( S )-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous l -Glu. ( R )-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, ( S )-2MeGlu was selectively converted to ( S )-2-methylglutamine, or ( S )-2MeGln, which was subsequently slowly hydrolyzed back to ( S )-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as ( S )-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of ( R )-2MeGlu, ( S )-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of ( R )-2MeGlu or ( S )-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport l -Gln.