Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid

Ionotropic glutamate teceptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carbox-yphenoxy)pyrrolidine-2-carboxylic acid (lb), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (K-i = 4 mu M). In a functional assay, lb displayed full antagonist activity with IC50 = 6 +/- 2 mu M. A cryatal structure was obtained of lb when bound in the ligand binding domain of GluKI. A domain opening of 13-14 degrees was seen compared to the structure with glutamate, consistent with 113 being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.