Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation

Antagonists addressing selectively NMDA receptors containing the GIuN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GIuN2B), Phel14 (GIuN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenyipropyl derivative 4a shows promising GluN2B affinity (K-i=101 nM) and high selectivity over the PCP binding site and both sigma receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC50 value of 5.2 mu M. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil. (C) 2017 Elsevier Masson SAS. All rights reserved.