4,4-Dimethyl- and diastereomeric 4-hydroxy-4-methyl- (2S)-glutamate analogues display distinct pharmacological profiles at ionotropic glutamate receptors and excitatory amino acid transporters.
Subtype-selective ligands are of great interest to the scientific community, as they provide a tool for investigating the function of one receptor or transporter subtype when functioning in its native environment. Several 4-substituted (S)-glutamate (Glu) analogues were synthesized, and altogether this approach has provided important insight into the structure-activity relationships (SAR) for ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs), as well as the excitatory amino acid transporters (EAATs). In this work, three 4,4-disubstituted Glu analogues 1-3, which are hybrid structures of important 4-substituted Glu analogues 4-8, were investigated at iGluRs and EAATs. Collectively, their pharmacological profiles add new and valuable information to the SAR for the iGluRs and EAAT1-3.
Bunch
Lennart
L
Department of Medicinal Chemistry, University of Copenhagen, Denmark. lebu@farma.ku.dk
Pickering
Darryl S
DS
Gefflaut
Thierry
T
Vinatier
Virginie
V
Helaine
Virgil
V
Amir
Ahmad
A
Nielsen
Birgitte
B
Jensen
Anders A
AA
D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000818:Animals; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008968:Molecular Conformation; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013329:Structure-Activity Relationship
D026905:Amino Acid Transport Systems; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid