title: Glutamate receptor agonists: stereochemical aspects.
abstract: The neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally α-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist binding pocket is filled, but also how it affects the conformational space of the ligand and in this way restricts the recognition of various glutamate receptors, ultimately leading to selectivity.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Stine Byskov
authors.initials: SB
authors.lastname: Vogensen
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Greenwood
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
authors.forename: Rasmus Prætorius
authors.initials: RP
authors.lastname: Clausen
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000502:physiology; D018360:Crystallography, X-Ray; D015195:Drug Design; D018690:Excitatory Amino Acid Agonists / Q000138:chemical synthesis / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D015870:Gene Expression; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D058468:Receptors, Ionotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014981:Xenopus
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D020033:Protein Isoforms; D058468:Receptors, Ionotropic Glutamate; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid