Pharmacological characterization of (4R)-alkyl glutamate analogues at the ionotropic glutamate receptors — Focus on subtypes iGlu5–7

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 KA1,2 and iGlu5–7. In the search for subtype selective ligands, α-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 iGlu5 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 iGlu5 receptor subtype (Ki = 20.5 nM) in comparison with its E-4-alkylidene structural isomer 2g. Furthermore, 1g displays high selectivity over other KA receptor subtypes (KA1,2 and iGlu6,7), AMPA-, and NMDA receptors (2050 and > 5000 fold, respectively).