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5 results on '"CCK1-R"'

1. Anthranilic acid based CCK1 receptor antagonists: Blocking the receptor with the same ‘words’ of the endogenous ligand

Author

Lassiani, Lucia, Pavan, Michela V., Berti, Federico, Kokotos, George, Markidis, Theodoros, Mennuni, Laura, Makovec, Francesco, and Varnavas, Antonio

Subjects
*AMINO acid synthesis, *CELL receptors, *CHOLECYSTOKININ, *CHEMICAL inhibitors, *LIGANDS (Biochemistry), *NEUROPEPTIDES, *STRUCTURE-activity relationships
Abstract

Abstract: The anthranilic acid diamides represent the more recent class of nonpeptide CCK1 receptor antagonists. This class is characterized by the presence of anthranilic acid, used as a molecular scaffold, and two pharmacophores selected from the C-terminal tetrapeptide of CCK. The lead compound coded VL-0395, endowed with sub-micromolar affinity towards CCK1 receptors, was characterized by the presence of Phe and 2-indole moiety at the C- and N-termini of anthranilic acid, respectively. Herein we describe the first step of the anthranilic acid C-terminal optimization using, instead of Phe, aminoacids belonging to the primary structure of CCK-8 and other not coded residues. Thus we demonstrate that the CCK1 receptor affinity depends on the nature of the aminoacidic side chain as well as that the free carboxy group of the alpha-aminoacids is crucial for the binding. The R enantiomers of the most active compounds represent the eutomers of this class of antagonists confirming thus the stereo preference of the receptor. Moreover this SAR study demonstrates that the receptor binding pocket, that host the aminoacidic side chain, results much more tolerant respect to that accommodating the indole ring. As a result, an appropriate variation of the aminoacidic side chain could provide a better CCK1 receptor affinity diorthosis. [Copyright &y& Elsevier]

Published
2009
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2. New anthranilic acid based antagonists with high affinity and selectivity for the human cholecystokinin receptor 1 (hCCK1-R)

Author

Federico Berti, Laura Mennuni, Lucia Lassiani, Flora Ferrari, Alessia Ciogli, Francesco Makovec, Daniel Fourmy, Antonio Varnavas, Chantal Escrieut, Giorgio Stefancich, Francesco Gasparrini, Esther Marco, Michela V. Pavan, Pavan, MICHELA VIOLETTA, Lassiani, Lucia, Berti, Federico, Stefancich, Giorgio, Ciogli, A., Gasparrini, F., Mennuni, L., Ferrari, F., Escrieut, C., Marco, E., Makovec, F., Fourmy, D., and Varnavas, Antonios

Subjects
Male, Models, Molecular, Indoles, CCK1-R, Cholecystokinin receptor, Rats, Sprague-Dawley, chemistry.chemical_compound, GALLBLADDER, DESIGN, Heterocyclic Compounds, CCK1 RECEPTOR, Chlorocebus aethiops, Receptors, Drug Discovery, Cholecystokinin, CCK, Ligands, Antagonists, Anthranilic acid, ortho-Aminobenzoates, Receptor, Cerebral Cortex, chemistry.chemical_classification, COS cells, Molecular Structure, DERIVATIVES, Aminobutyrates, digestive, oral, and skin physiology, PROTEIN-COUPLED-RECEPTOR, Amino acid, PROTEIN-COUPLED-RECEPTOR, CCK1 RECEPTOR, DERIVATIVES, LIGANDS, AGONIST, DENSITY, DESIGN, GALLBLADDER, RESOLUTION, STRATEGIES, AGONIST, Biochemistry, COS Cells, Molecular Medicine, LIGANDS, hormones, hormone substitutes, and hormone antagonists, Muscle Contraction, Agonist, STRATEGIES, Stereochemistry, medicine.drug_class, Guinea Pigs, Ligand, In Vitro Techniques, Binding, Competitive, digestive system, Sincalide, Structure-Activity Relationship, medicine, Animals, Humans, Structure–activity relationship, Binding site, Pancreas, Binding Sites, Antagonist, Rats, Receptor, Cholecystokinin A, chemistry, RESOLUTION, DENSITY, Mutation, Mutagenesis, Site-Directed
Abstract

The anthranilic acid diamides represent the most recent class of nonpeptide CCK(1) receptor (CCK(1)-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 CCK(1)-R affinity and 15-fold for the human CCK(1)-R relative to the reference compound 12 (VL-0395). The eutomer of 2 (6) exhibited a nanomolar range affinity toward the human CCK(1)-R and was at least 400-fold selective for the CCK(1)-R over the CCK(2)-R. Molecular docking in the modeled CCK(1)-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 CCK(1)-R antagonists.

Published
2011

3. Anthranilic acid based CCK1 antagonists: the 2-indole moiety may represent a 'needle' according to the recent homonymous concept

Author

Antonio Varnavas, Francesco Makovec, Laura Mennuni, Valentina Valenta, Andrea Tontini, Lucia Lassiani, Federico Berti, Varnavas, Antonio, Lassiani, Lucia, Valenta, Valentina, Berti, Federico, Tontini, A., Mennuni, L., and Makovec, F.

Subjects
Male, Models, Molecular, Indoles, Molecular model, Stereochemistry, Guinea Pigs, Molecular Conformation, CCK1-R, Chemical synthesis, Cholecystokinin receptor, Binding, Competitive, Rats, Sprague-Dawley, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Receptors, Anthranilic acid, Moiety, Animals, ortho-Aminobenzoates, Receptor, Pancreas, Pharmacology, Indole test, Cerebral Cortex, CCK, antagonist, Organic Chemistry, Cell Membrane, General Medicine, Rats, Receptor, Cholecystokinin A, chemistry, Lead compound
Abstract

Recently we described an innovative class of non-peptide CCK 1 antagonists keeping appropriate pharmacophoric groups on the anthranilic acid employed as a molecular scaffold. The lead compound obtained, VL-0395 , characterized by the presence of Phe and the 2-indole moiety at the C- and N-termini of anthranilic acid, respectively, is endowed with submicromolar affinity towards CCK 1 receptors. Thus, we have prepared and tested on CCK receptors a library of VL-0395 analogues in order to investigate the precise topological and essential key interactions of the 2-indole group of the lead with the CCK 1 receptor. The obtained results confirm that this group establishes very specific interactions with this receptor sub-site and may be viewed as a “needle” group.

Published
2004

4. Anthranilic acid derivatives: A new class of non-peptide CCK1 receptor antagonists

Author

Antonio Varnavas, Francesco Makovec, Laura Mennuni, Valentina Valenta, Lucia Lassiani, Federico Berti, Varnavas, Antonio, Lassiani, Lucia, Valenta, V, Berti, Federico, Mennuni, L, and Makovec, F.

Subjects
Models, Molecular, Molecular model, Stereochemistry, Dimer, Clinical Biochemistry, Guinea Pigs, Molecular Conformation, Pharmaceutical Science, CCK1-R, Biochemistry, Cholecystokinin receptor, Rats, Sprague-Dawley, chemistry.chemical_compound, Residue (chemistry), Structure-Activity Relationship, Drug Discovery, Receptors, Anthranilic acid, Animals, ortho-Aminobenzoates, Receptor, Molecular Biology, Pancreas, Indole test, Cerebral Cortex, Organic Chemistry, CCK, ANTHRANYLIC ACID, Rats, Receptor, Cholecystokinin A, chemistry, Molecular Medicine, Indicators and Reagents, Receptors, Cholecystokinin, Spectrophotometry, Ultraviolet, Chromatography, Thin Layer, Lead compound
Abstract

Having successfully obtained new CCK 1 ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK 1 receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N -substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK 1 receptor binding affinity (compound 1 : IC 50 =197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound ( 1 ) (coded VL-0395 ) a receptor binding hypothesis has been provided.

Published
2003

5. Synthesis of N-terminal substituted anthranilic acid dimer derivatives for evaluation on CCK receptors

Author

Lucia Lassiani, Antonio Varnavas, Valentina Valenta, Federico Berti, Varnavas, Antonio, Valenta, Valentina, Berti, Federico, and Lassiani, Lucia

Subjects
Models, Molecular, Molecular model, Stereochemistry, Dimer, Guinea Pigs, Pharmaceutical Science, CCK1-R, Chemical synthesis, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Receptors, Anthranilic acid, Structure–activity relationship, Animals, ortho-Aminobenzoates, antagonist, ANTHRANYLIC ACID, CCK, Benzodiazepinones, Tetrapeptide, Asperlicin, Ligand (biochemistry), Rats, chemistry, Receptors, Cholecystokinin, Dimerization, Receptor
Abstract

A series of new N-substituted anthranilic acid dimer derivatives having a C-terminal Phe residue was synthesized and evaluated for their affinity for CCK receptors. These compounds resulted from a blended approach based firstly on the use of an alternative substructure embedded within asperlicin and secondly on the derivatization of this template with substituents chosen considering the C-terminal primary structure of the endogenous ligand. Although these compounds exhibited a regnylogical-type organization similar to that of CCK-4, they are characterized by about 1000-fold greater affinity for CCK-A receptor than the C-terminal tetrapeptide.

Published
2001

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