Design and characterization of dimeric ligands cross-linking two identical modulatory AMPA receptor sites

MEDI 277

Birgitte H. Kaae, bhk@farma.ku.dk1, Kasper Harpsøe1, Alberto Contreras Sanz2, Darryl S. Pickering2, Per Sauerberg3, Rasmus P. Clausen1, Jette S. Kastrup1, Tommy Liljefors1, and Ulf Madsen1. (1) Dept. of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark, (2) Dept. of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark, (3) Medicinal Chemistry Research II, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måloev, Denmark
AMPA receptors belong to the class of excitatory amino acid receptors, and play important roles in physiological functions, and in many neurological disorders. E.g. modulators are of great therapeutic interest as cognitive enhancers. AMPA receptors are composed of four subunits assembled as two subunit-dimers. Ligands were designed to cross-link two identical modulatory binding sites by the use of computational chemistry. The designed dimeric ligands were synthesized in excellent yields. Pharmacological characterization of these allosteric positive modulators revealed potent EC50 values (0.5-3.5 µM) on GluR1i-4i, and no subunit selectivity. The preferred stereoisomer was co-crystallized with (S)-glutamate and GluR2-S1S2J (N754S), and the x-ray structure revealed cross-linking of two identical binding sites by the dimeric ligand as predicted.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007