Neurotoxic potential of three structural analogs of beta-N-oxalyl-alpha,beta-diaminopropanoic acid (beta-ODAP).
Lathyrism is a non-progressive motor neuron disease produced by consumption of the excitatory amino acid, 3-N-oxalyl-L-2,3-diaminopropanoic acid (beta-ODAP). To learn more about the mechanisms underlying Lathyrism three structural analogs of beta-ODAP were synthesized. Carboxymethyl-alpha,beta-diaminopropanoic acid (CMDAP) evoked inward currents which were antagonized by APV (30 microM), but not by CNQX (10 microM). N-acetyl-alpha,beta-diaminopropanoic acid (ADAP) evoked no detectable ionic currents but potentiated N-methyl-D-aspartate (NMDA)-activated currents. The potentiation of NMDA currents by ADAP was blocked by 7-chlorokynurenic acid. Carboxymethylcysteine (CMC) did not activate any detectable ionic currents. None of the three beta-ODAP analogs produced visible symptoms of toxicity in day old chicks when administered for 2-3 consecutive days. Ligand binding studies demonstrated that all the three compounds were effective to in displacing [3H]glutamate. The maximum inhibition was 92% for CMDAP, 61% for ADAP, 65% for CMC and 99% for beta-ODAP. These data indicate that analogs of beta-ODAP may interact with glutamate receptors without producing neurotoxicity.
Omelchenko
I A
IA
Center for Research on Occupational and Environmental Toxicology, Oregon Health Sciences University, Portland 97201-3098, USA.
Jain
R K
RK
Junaid
M A
MA
Rao
S L
SL
Allen
C N
CN
D000599:Amino Acids, Diamino / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
D000599:Amino Acids, Diamino; D009498:Neurotoxins; C100126:oxalyldiaminopropionic acid