The anthranilic acid diamides represent the most recent class of nonpeptide CCK1 receptor (CCK1-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK1-R affinity and 15-fold for the human CCK1-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK1-R and was at least 400-fold selective for the CCK1-R over the CCK2-R. Molecular docking in the modeled CCK1-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK1-R antagonists.

New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R) / M. V., Pavan; L., Lassiani; F., Berti; G., Stefancich; Ciogli, Alessia; Gasparrini, Francesco; L., Mennuni; F., Ferrari; C., Escrieut; E., Marco; F., Makovec; D., Fourmy; A., Varnavas. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 54:(2011), pp. 5769-5785. [10.1021/jm200438b]

New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R)

CIOGLI, Alessia;GASPARRINI, Francesco;
2011

Abstract

The anthranilic acid diamides represent the most recent class of nonpeptide CCK1 receptor (CCK1-R) antagonists. Herein we describe the second phase of the anthranilic acid C-terminal optimization using nonproteinogenic amino acids containing a phenyl ring in their side chain. The Homo-Phe derivative 2 (VL-0797) enhanced 12-fold the affinity for the rat CCK1-R affinity and 15-fold for the human CCK1-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK1-R and was at least 400-fold selective for the CCK1-R over the CCK2-R. Molecular docking in the modeled CCK1-R and its validation by site-directed mutagenesis experiments showed that the 6 binding site overlaps that occupied by the C-terminal bioactive region of the natural agonist CCK. Owing to their interesting properties, new compounds provided by this study represent a solid basis for further advances aimed at synthesis of clinically valuable CCK1-R antagonists.
2011
PROTEIN-COUPLED-RECEPTOR, CCK1 RECEPTOR, DERIVATIVES, LIGANDS, AGONIST, DENSITY, DESIGN, GALLBLADDER, RESOLUTION, STRATEGIES
01 Pubblicazione su rivista::01a Articolo in rivista
New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R) / M. V., Pavan; L., Lassiani; F., Berti; G., Stefancich; Ciogli, Alessia; Gasparrini, Francesco; L., Mennuni; F., Ferrari; C., Escrieut; E., Marco; F., Makovec; D., Fourmy; A., Varnavas. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 54:(2011), pp. 5769-5785. [10.1021/jm200438b]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/390098
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