Abstract
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.
Highlights
Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders
In addition to 2MeGlu, we evaluated its hypothetical metabolites, i.e., analogues of the major Glu metabolites methylated at the carbon atom located at the α position in Glu; these include: 2-methylglutamine (2MeGln, the Gln analogue), 4-aminopentanoic acid (4APA, the Gln would impact the γ-aminobutyric acid (GABA) analogue), 4OPA (4-oxopentanoic acid or levulinic acid, the SSA analogue), and 4-hydroxypentanoic acid (4HPA, the GHB analogue). α-KG and SA have no corresponding methylated analogues; the presence of the hypothetical carbon atom at the α position would not be possible without breaking the existing C–C bonds
Introduction of a methyl group on the α carbon drastically reduced the ability of the stationary phase to resolve enantiomers compared to natural amino acids, we achieved baseline resolution of 2MeGlu and 4APA enantiomers without prior derivatization (Supplementary Figure S1)
Summary
Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. The prospect of restoring balance to these opposing systems has been the focus of many candidate therapeutics, some of which have gone on to wide-spread clinical application: receptor specific agonists, antagonists, and allosteric modulators, transporter inhibitors, gene transfer, and most recently cell therapy[10,11] None of these approaches target the metabolic balance of the GABA shunt or the glutamate-glutamine cycle, and as yet none has had a major impact on alleviating the common psychiatric or neurodegenerative diseases listed above. We tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of l-glutamate or l-glutamine would provide novel tools to modulate the metabolic balance within the the GABA shunt or the glutamate-glutamine cycle, and perhaps have utility as molecular imaging agents or drugs that influence behavior. Since α-KG and SA connect Glu to the Krebs cycle, 2MeGlu cannot enter the cycle in a Glu-like manner
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