title: Pharmacological characterization of (4R)-alkyl glutamate analogues at the ionotropic glutamate receptors--focus on subtypes iGlu(5-7).
abstract: The kainic acid (kainate, KA) receptors belong to the class of ionotropic glutamate (iGlu) receptors in the central nervous system. Five subtypes have been identified, which have been termed KA(1,2) and iGlu(5-7). In the search for subtype selective ligands, alpha-amino-5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), (4R)-methyl Glu (1a), and E-4-neopentylidene Glu (2f) have all previously been reported as selective agonists for the iGlu(5) receptor subtype. In this paper, we present the pharmacological evaluation of a five-compound series of (4R)-alkyl Glu analogs (1b-e,g) which may be envisaged as conformationally released designs of ATPA and 4-alkylidenes 2a-h. Most notable is the pharmacological profile for (4R)-isopentyl Glu (1g) which shows a 10-fold increase in binding affinity for the iGlu(5) receptor subtype (K(i)=20.5 nM) in comparison with its E-4-alkylidene structural isomer 2g. Furthermore, 1g displays high selectivity over other KA receptor subtypes (KA(1,2) and iGlu(6,7)), AMPA-, and NMDA receptors (2050 and >5000 fold, respectively).
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. lebu@farma.ku.dk
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
authors.forename: Thierry
authors.initials: T
authors.lastname: Gefflaut
authors.forename: Sebastien
authors.initials: S
authors.lastname: Alaux
authors.forename: Emanuelle
authors.initials: E
authors.lastname: Sagot
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
mesh_terms: D000818:Animals; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011422:Propionates / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011422:Propionates; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D007608:Kainic Acid