D. Meoh, following procedure C2 using benzyl-indole-C4-TFA 84 (286 mg, 0.58 mmol) DIEA (111 µL, 0.64 mmol), N?-Boc-L-Tryptophane (CAS: 144599-95-1) (194 mg, 0.64 mmol), CDI (112 mg, 0.70 mmol), DMF (3 mL + 6 mL) as a yellow crude oil, Biligand 91 was obtained, p.9

D. Meoh, following procedure C2 using benzyl-indole-C2-TFA 85 (150 mg, 0.32 mmol) DIEA (61 µL, 0.35 mmol), N?-Boc-L-Phenylalanine (CAS: 13734-34-4) (93 mg, 0.35 mmol, CDI (62 mg, 0.38 mmol), DMF (2 mL + 5 mL) as a yellow crude oil (96 mg, 0.16 mmol, 50%), p.9

N. Dimethylquinoline, . Ho, and . Oh, 7 g/mol Quinoline 195 (93 mg, 0.32 mmol) was engaged with MeOH (15 mL) and KOH (0.179 g, 3.2 mmol, 10 eq.) and heated to reflux for 24 h. The mixture was neutralized with HCl (1 M). The solvent was removed and the residue was purified by filtration HCl (3 M) through a column of Amberlite® (IRA-401), p.37

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P. Les-protéines-À-domaine, en très grand nombre dans le génome humain, sont impliquées dans des interactions protéine-protéine. Elles participent ainsi à véhiculer des signaux à l'origine de différentes pathologies (cancer, douleur?.). L'interruption de l'interaction entre la protéine à domaine PDZ, PSD-95, et le récepteur de la sérotonine, 5-HT2A, entraîne une réduction de l'hyperalgie chez le rat neuropathique

. Nous-avons-réalisé, au cours de ces travaux, la synthèse de trois générations de ligands, comportant un noyau indolique, capables d'interagir avec le site S0

. Dans-un-premier and . Temps, nous avons préparé 15 biligands possédant un noyau indolique polysubstitué lié, via un espaceur de longueur variable (2 à 6 atomes de carbone), à différents acides aminés, dans le but d'interagir avec le site S1, montrant beaucoup de diversité en fonction du domaine. Nous avons ensuite, après une étude de relation structure/activité

. Nous-avons-montré, et chromatographie d'affinité, que deux de ces composés sont des inhibiteurs de l'interaction PSD-95/5-HT2A et présentent de fortes interactions avec le site S0 de PSD-95. Ces molécules présentent également des propriétés antalgiques particulièrement intéressantes in vivo. Nous avons également déterminé, par RMN NOESY, la structure du complexe protéine/ligand pour ces deux composés. L'orientation d'une de ces molécules dans le site de la protéine nous permet d'envisager le développement d'une nouvelle génération d'indoles polysubstitués, pp.5-7