A Novel Series of 2-Carboxytetrahydroquinolines Provides New Insights into the Eastern Region of Glycine Site NMDA Antagonists

Abstract

A series of potent 4‐substituted tetrahydroquinolines has been synthesized and biologically tested in order to refine the eastern region of the pharmacophore model for glycine site NMDA antagonists concerning the assessment of lipophilicity, flexibility, and hydrogen bonding. Displacement studies on rat cortical mem‐branes using [3H]‐5,7‐dichlorokynurenic acid as a radioligand indicated that binding affinities are markedly enhanced when additional hydrogen‐accepting groups are introduced into the east‐ern region of the 2‐carboxytetrahydroquinolines. Among the most potent ligands were some urea, sulfonylurea, and crown ether compounds as interesting leads for new diagnostics, especially for the evaluation of PET tracers, which allow biodistribution studies and NMDA receptor studies in the living organism.

Comparative virtual screening and novelty detection for NMDA-GlycineB antagonists

“…We used the structure of the low nanomolar compound [67] 7 as a reference for a 3D shape search applying Schrödinger's Phase. The probable isomerization state was assessed at pH 7.4 using Epik 1.6 and the corresponding 3D structure was energy-minimized using MacroModel 9.6 (Schrödinger, LLC, New York, 2008) (OPLS2005, Generalized Born implicit solvent model, constant dielectric treatment of 1.0 and gradient-descent convergence after 1,000 iterations).…”