Exploring the GluR2 ligand‐binding core in complex with the bicyclical AMPA analogue (S)‐4‐AHCP

The X‐ray structure of the ionotropic GluR2 ligand‐binding core (GluR2‐S1S2J) in complex with the bicyclical AMPA analogue (S)‐2‐amino‐3‐(3‐hydroxy‐7,8‐dihydro‐6H‐cyclohepta[d]‐4‐isoxazolyl)propionic acid [(S)‐4‐AHCP] has been determined, as well as the binding pharmacology of this construct and of the full‐length GluR2 receptor. (S)‐4‐AHCP binds with a glutamate‐like binding mode and the ligand adopts two different conformations. The Ki of (S)‐4‐AHCP at GluR2‐S1S2J was determined to be 185 ± 29 nm and at full‐length GluR2(R)o it was 175 ± 8 nm. (S)‐4‐AHCP appears to elicit partial agonism at GluR2 by inducing an intermediate degree of domain closure (17°). Also, functionally (S)‐4‐AHCP has an efficacy of 0.38 at GluR2(Q)i, relative to (S)‐glutamate. The proximity of bound (S)‐4‐AHCP to domain D2 prevents full D1–D2 domain closure, which is limited by steric repulsion, especially between Leu704 and the ligand.