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Cycloalkyl Indole‐2‐Carboxylates as Useful Tools for Mapping the "North‐Eastern" Region of the Glycine Binding Site Associated with the NMDA Receptor
Author(s) -
Micheli Fabrizio,
Di Fabio Romano,
Capelli Anna M.,
Cugola Alfredo,
Curcuruto Ornella,
Feriani Aldo,
Gastaldi Paola,
Gaviraghi Giovanni,
Marchioro Carla,
Orlandi Alessandra,
Pozzan Alfonso,
Quaglia Anna M.,
Reggiani Angelo,
van Amsterdam Frank
Publication year - 1999
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(19993)332:3<73::aid-ardp73>3.0.co;2-5
Subject(s) - nmda receptor , glycine , chemistry , stereochemistry , indole test , ampa receptor , binding site , strychnine , glycine receptor , carboxylic acid , antagonist , amino acid , receptor , biochemistry
A novel series of indole‐2‐carboxylate analogues of GV150526 ( 1 ) in which the terminal phenyl ring belonging to the side chain present in the position C‐3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophilic pocket present in the "North‐Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the derivatives prepared, 3‐[2‐(1‐adamantylaminocarbonyl) ethenyl]‐4,6‐dichloroindole‐2‐carboxylic acid 6b and 3‐[2‐(norbornylaminocarbonyl)ethenyl]‐4,6‐dichloroindole‐2‐carboxylic acid 6l were found to be antagonists acting at the strychnine‐insensitive glycine binding site, showing nanomolar affinity for the glycine binding site ( K i = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC 50 >10 ‐5 M at the NMDA, AMPA, KA binding sites) and high in vivo potency after systemic administration by inhibition of convulsion induced by NMDA in mice.