title: Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site.
abstract: 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.
authors.affiliation: Glaxo Wellcome S.p.A., Medicines Research Centre, Verona, Italy. rdf26781@ggr.co.uk
authors.forename: R
authors.initials: R
authors.lastname: Di Fabio
authors.forename: A M
authors.initials: AM
authors.lastname: Capelli
authors.forename: N
authors.initials: N
authors.lastname: Conti
authors.forename: A
authors.initials: A
authors.lastname: Cugola
authors.forename: D
authors.initials: D
authors.lastname: Donati
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 T
authors.initials: CT
authors.lastname: Hewkin
authors.forename: F
authors.initials: F
authors.lastname: Micheli
authors.forename: A
authors.initials: A
authors.lastname: Missio
authors.forename: M
authors.initials: M
authors.lastname: Mugnaini
authors.forename: A
authors.initials: A
authors.lastname: Pecunioso
authors.forename: A M
authors.initials: AM
authors.lastname: Quaglia
authors.forename: E
authors.initials: E
authors.lastname: Ratti
authors.forename: L
authors.initials: L
authors.lastname: Rossi
authors.forename: G
authors.initials: G
authors.lastname: Tedesco
authors.forename: D G
authors.initials: DG
authors.lastname: Trist
authors.forename: A
authors.initials: A
authors.lastname: Reggiani
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002264:Carboxylic Acids; D002540:Cerebral Cortex / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018684:Glycine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000494:pharmacology
chemical_list: C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D002264:Carboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D018684:Glycine Agents; D007211:Indoles; D017470:Receptors, Glutamate; C058980:indole-2-carboxylic acid; D016202:N-Methylaspartate; D013331:Strychnine; D005998:Glycine