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

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...

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Bibliographic Details
Published in:	Archiv der Pharmazie (Weinheim) Vol. 333; no. 8; pp. 267 - 274
Main Authors:	Dannhardt, Gerd, v. Gruchalla, Markus, Kohl, Beate K., Parsons, C. G.
Format:	Journal Article
Language:	English
Published:	Weinheim WILEY-VCH Verlag GmbH 01-08-2000 WILEY‐VCH Verlag GmbH Wiley-VCH
Subjects:	2-carboxytetrahydroquinolines Animals Binding Sites Biological and medical sciences Brain - ultrastructure Cell Membrane - chemistry Cell Membrane - metabolism crown ether compounds eastern region Ethers, Cyclic - metabolism Ethers, Cyclic - pharmacology Excitatory Amino Acid Antagonists - metabolism Glutamatergic system (aspartate and other excitatory aminoacids) Glycine - chemistry Glycine - metabolism Kynurenic Acid - analogs & derivatives Kynurenic Acid - metabolism Male Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors NMDA receptor binding studies patch clamp studies Patch-Clamp Techniques Pharmacology. Drug treatments Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - metabolism relationships structure-activity sulfonylureas Urea - analogs & derivatives Urea - metabolism Urea - pharmacology ureas Rat Nitrogen heterocycle Rodentia Central nervous system Crown compound Glutamate receptor In vitro α-Aminoacid Vertebrata Mammalia Structure activity relation Chlorine Organic compounds Animal Glycine receptor Sulfonylureas Bicyclic compound Affinity Ureas Aromatic compound Antagonist NMDA receptor Chemical synthesis Brain (vertebrata)
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Summary:	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.
Bibliography:	istex:E689F5CACD57AF1B4CF7EE623D5E9FA8CAFFA69B ark:/67375/WNG-M99X6GM4-H ArticleID:ARDP267 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0365-6233 1521-4184
DOI:	10.1002/1521-4184(20008)333:8<267::AID-ARDP267>3.0.CO;2-0