title: Cycloalkyl indole-2-carboxylates as useful tools for mapping the "north-eastern" region of the glycine binding site associated with the NMDA receptor.
abstract: A novel series of indole-2-carboxylate analogues of GV 150526 (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-c arboxylic acid 6l were found to be antagonists acting at the strychnine-insensitive glycine binding site, showing nanomolar affinity for the glycine binding site (Ki = 63 and 19 nM, respectively), coupled with high glutamate receptor selectivity (IC50 > 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.
authors.affiliation: Glaxo Wellcome S.p.A., Medicines Research Centre, Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Micheli
authors.forename: R
authors.initials: R
authors.lastname: Di Fabio
authors.forename: A M
authors.initials: AM
authors.lastname: Capelli
authors.forename: A
authors.initials: A
authors.lastname: Cugola
authors.forename: O
authors.initials: O
authors.lastname: Curcuruto
authors.forename: A
authors.initials: A
authors.lastname: Feriani
authors.forename: P
authors.initials: P
authors.lastname: Gastaldi
authors.forename: G
authors.initials: G
authors.lastname: Gaviraghi
authors.forename: C
authors.initials: C
authors.lastname: Marchioro
authors.forename: A
authors.initials: A
authors.lastname: Orlandi
authors.forename: A
authors.initials: A
authors.lastname: Pozzan
authors.forename: A M
authors.initials: AM
authors.lastname: Quaglia
authors.forename: A
authors.initials: A
authors.lastname: Reggiani
authors.forename: F
authors.initials: F
authors.lastname: van Amsterdam
mesh_terms: D000547:Amantadine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D016202:N-Methylaspartate / Q000494:pharmacology; D009636:Norbornanes / Q000138:chemical synthesis* / Q000494:pharmacology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced
chemical_list: C119670:3-(2-(1-adamantylaminocarbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; C119686:3-(2-(norbornylaminocarbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D008024:Ligands; D009636:Norbornanes; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D000547:Amantadine