Substituted Indole-2-carboxylates as in Vivo Potent Antagonists Acting as the Strychnine-Insensitive Glycine Binding Site
| Autor: | Luciana Rossi, A. Feriani, Fabrizio Micheli, Anna M. Quaglia, Anna-Maria Capelli, David G. Trist, Paola Gastaldi, Angelo Reggiani, Alfredo Cugola, E. Ratti, Daniele Donati, Angelo Pecunioso, Manolo Mugnaini, Cheryl T. Hewkin, R. Di Fabio, Nadia Conti, Giovanna Tedesco, Andrea Missio, Giovanni Gaviraghi |
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| Rok vydání: | 1997 |
| Předmět: |
Indoles
Magnetic Resonance Spectroscopy N-Methylaspartate Stereochemistry Carboxylic Acids Glycine Kainate receptor Binding Competitive Mice Structure-Activity Relationship chemistry.chemical_compound Glycine binding Non-competitive inhibition Drug Discovery Animals Binding site Glycine receptor Cerebral Cortex Indole test Binding Sites Molecular Structure Chemistry Glycine Agents Strychnine Rats Receptors Glutamate Molecular Medicine NMDA receptor Excitatory Amino Acid Antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 40:841-850 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor. |
| Databáze: | OpenAIRE |
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