Pyridine bioisosteres of potent GluN2B subunit containing NMDA receptor antagonists with benzo[7]annulene scaffold

Abstract

It has been reported that benzo [7]annulen-7-amines bearing electron withdrawing substituents such as 3d with a 2-Cl or 3e with a 2-NO2 moiety show very high affinity towards the ifenprodil binding site of GluN2B subunit containing NMDA receptors. Therefore, bioisosteres of 3 with an electron deficient pyridine ring instead of the chloro- or nitrobenzene ring were envisaged. Starting from pyridine-2,3-dicarboxylic acid (5) a five-step synthesis of the key intermediate, the ketone 10, was developed. Reductive amination with various primary amines and NaBH(OAc)3 led to the homologous secondary amines 11a-c. Subsequent methylation yielded the tertiary amines 12b and 12c. Receptor binding studies with [3H]ifenprodil revealed Ki-values above 100 nM for the most active phenylpropyl- and phenylbutylamines 11b and 11c. The >100-fold reduced GluN2B affinity of pyridines 11b and 11c compared to the GluN2B affinity of the corresponding chloro- and nitrobenzene derivatives 3d and 3e indicates that the pyridine ring is not tolerated as bioisosteric replacement of the chloro- or nitrobenzene ring in this type of compounds.