Cis-2,4-methanoglutamate is a potent and selective N-methyl-D-aspartate receptor agonist.
Cis- and trans-2,4-methanoglutamate were compared with L-glutamate as acidic amino acid ligands. Cis-2,4-methanoglutamate had a Ki of 0.052 microM against N-methyl-D-aspartate (NMDA)-specific L-[3H]glutamate binding compared with 0.050 microM for L-glutamate. Cis-2,4-methanoglutamate exhibited no significant affinity against [3H]kainate or [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate ([3H]AMPA) binding. Trans-2,4-methanoglutamate had no significant affinity for any of these sites. Cis-2,4-methanoglutamate increased [3H]N-1[2-thienyl]cyclohexyl-3,4-piperidine [( 3H]TCP) binding with EC50 of 0.35 +/- 0.14 microM. It produced an inward current in rat brain mRNA-injected Xenopus oocytes which was blocked by the NMDA antagonist, D-2-amino-7-phosphonoheptanoate (D-AP7). Cis-2,4-methanoglutamate (EC50 = 15.9 microM) was 100-fold more potent than L-glutamate (EC50 = 1,584 microM) in reducing the excitatory postsynaptic potential in CA1 of hippocampal slices. Cis-2,4-methanoglutamate is the most potent, selective NMDA agonist known.
Lanthorn
T H
TH
CNS Diseases Research, G.D. Searle & Co., St. Louis, MO.
Hood
W F
WF
Watson
G B
GB
Compton
R P
RP
Rader
R K
RK
Gaoni
Y
Y
Monahan
J B
JB
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D004558:Electric Stimulation; D004594:Electrophysiology; D005971:Glutamates / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009865:Oocytes / Q000187:drug effects; D012333:RNA, Messenger / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D013237:Stereoisomerism; D013570:Synaptic Membranes / Q000187:drug effects; D014982:Xenopus laevis
D000596:Amino Acids; D000927:Anticonvulsants; D005971:Glutamates; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C066302:2,4-methanoglutamate; D015763:2-Amino-5-phosphonovalerate; C031231:2-amino-7-phosphonoheptanoic acid