Synthesis, absolute configuration and activity at N-methyl-D-aspartic acid (NMDA) receptor of the four D-2-amino-4,5-methano-adipate diastereoisomers.
The four D-2-amino-4,5-methano-adipates 26, 27, 32, 33 were synthesized and their biological activity at the N-methyl-D-aspartate (NMDA) receptor was assessed. The synthesis involved as a key step a rhodium acetate dimer catalyzed addition of ethyl diazoacetate to the protected D-allylglycine (17). In vitro receptor binding using L-[3H]glutamate as the radioligand provided affinity data, while modulation of [3H]TCP binding was used as a functional assay. The analogues were also evaluated in [3H]kainate and [3H]AMPA binding to assess selectivity over non-NMDA glutamate receptors. Three of the four diastereoisomer, D-CAA B (27), C (32) and D (33) were shown to have agonist properties at the NMDA-site, while the fourth, (2R,4R,5R) D-CAA A (26) was characterized as an NMDA-site atypic antagonist.
Pellicciari
R
R
Istituto di Chimica Farmaceutica e Tecnica Farmaceutica, Università Degli Studi, Perugia, Italy.
Natalini
B
B
Marinozzi
M
M
Sadeghpour
B M
BM
Cordi
A A
AA
Lanthorn
T H
TH
Hood
W F
WF
Monahan
J B
JB
D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D066298:In Vitro Techniques; D008968:Molecular Conformation; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013237:Stereoisomerism; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism
D015074:2-Aminoadipic Acid; D010622:Phencyclidine; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C074439:2-amino-4,5-methanoadipate; C012058:tenocyclidine