Neuroactive carbamate adducts of beta-N-methylamino-L-alanine and ethylenediamine. Detection and quantitation under physiological conditions by 13C NMR.
beta-N-Methylamino-L-alanine (BMAA) reacts with dissolved carbon dioxide to form two carbamate compounds at physiological pH, temperature and bicarbonate concentration. The reversible reactions of BMAA with dissolved carbon dioxide were monitored by 13C NMR. At 37 degrees C and pH 7.4, the fraction of BMAA existing as the alpha-N-carboxy adduct is 0.22 while the fraction of BMAA existing as the beta-N-carboxy adduct is 0.09. Although both adducts could be implicated in the bicarbonate-dependent neurotoxicity of BMAA (Weiss, J. H., and Choi, D. W. (1988) Science 241, 973-975; Mroz, E. A., Weiss, J. W., and Choi, D. W. (1989) Science 243, 1613), the beta-N-carboxy adduct shares structural characteristics with the appropriate endogenous ligand, glutamic acid. Analogously, the GABA-mimetic properties of ethylenediamine have been attributed to a carbamate adduct, ethylenediamine monocarbamate (Kerr, D. I. B., and Ong, J. (1987) Br. J. Pharmacol. 90, 763-769). Using the same method, we were able to detect directly and quantify the formation of this carbamate under physiological conditions. Information on the carbamate equilibria of these compounds is essential in order to address questions of their neuroactive potency.
Myers
T G
TG
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
Nelson
S D
SD
D000599:Amino Acids, Diamino / Q000138:chemical synthesis*; D000600:Amino Acids, Dicarboxylic / Q000138:chemical synthesis*; D001639:Bicarbonates; D002219:Carbamates; D002245:Carbon Dioxide; D002247:Carbon Isotopes; D000087522:Cyanobacteria Toxins; D005029:Ethylenediamines; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D009498:Neurotoxins
D000599:Amino Acids, Diamino; D000600:Amino Acids, Dicarboxylic; D001639:Bicarbonates; D002219:Carbamates; D002247:Carbon Isotopes; D000087522:Cyanobacteria Toxins; D005029:Ethylenediamines; D009498:Neurotoxins; C001824:beta-N-methylamino-L-alanine; C064612:alpha-N-carboxy-beta-N-methylaminoalanine; C064614:beta-(N-carboxy-N-methyl)aminoalanine; D002245:Carbon Dioxide