Lennart Bunch
University of Copenhagen, Denmark
Posters & Accepted Abstracts: Med Chem (Los Angeles)
Ionotropic glutamate receptor antagonists are highly 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- carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki=4 �¼M). In a functional assay 1b displayed full antagonist activity with IC50=6�±2 �¼M. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14�ºC was seen compared to the structure with glutamate, consistent with 1b 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. The talk will also cover results from other design studies which have led to successes as well as failures in this field.
Email: lebu@sund.ku.dk
Medicinal Chemistry received 6627 citations as per Google Scholar report