Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

García-López, M. Teresa; González‐Muñiz, Rosario; Martı́n-Martı́nez, Mercedes; Herranz, Rosario

doi:10.2174/156802607780960537

Cited by 13 publications

(1 citation statement)

References 86 publications

(127 reference statements)

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“…Devazepide (L-364,718 or MK-329) is a potent nonpeptide CCK antagonist selective for the CCK-1 receptor (CCK-1R) subtype and is structurally derived from the benzodiazepine family, but with quite different actions from most benzodiazepines [8][9][10]. It increases appetite and accelerates gastric emptying [11,12] and may act as a potential drug for the treatment of a variety of gastrointestinal disorders [13].…”

Section: Introductionmentioning

confidence: 99%

The cholecystokinin‐1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice

Wang

Portincasa

Wang

2016

Eur J Clin Investigation

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Background A defect in gallbladder contraction function plays a key role in the pathogenesis of gallstones. The cholecystokinin-1 receptor (CCK-1R) antagonists have been extensively investigated for their therapeutic effects on gastrointestinal and metabolic diseases in animal studies and clinical trials. However, it is still unknown whether they have a potential effect on gallstone formation. Design To study whether the CCK-1R antagonists enhances cholelithogenesis, we investigated cholesterol crystallization, gallstone formation, hepatic lipid secretion, gallbladder emptying function, and intestinal cholesterol absorption in male C57BL/6J mice treated by gavage with devazepide (4 mg/day/kg) or vehicle (as controls) twice per day and fed the lithogenic diet for 21 days. Results During 21 days of feeding, oral administration of devazepide significantly accelerated cholesterol crystallization and crystal growth to microlithiasis, with 40% of mice forming gallstones. Whereas, only agglomerated cholesterol monohydrate crystals were found in mice receiving vehicle. Compared to the vehicle group, fasting and postprandial residual gallbladder volumes in response to the high-fat meal were significantly larger in the devazepide group during cholelithogenesis, showing reduced gallbladder emptying and bile stasis. Moreover, devazepide significantly increased hepatic secretion of biliary cholesterol, but not phospholipids or bile salts. The percentage of intestinal cholesterol absorption was higher in devazepide-treated mice, increasing bioavailability of chylomicron-derived cholesterol in the liver for biliary hypersecretion into bile. These abnormalities induced supersaturated bile and rapid cholesterol crystallization. Conclusions The potent CCK-1R antagonist devazepide increases susceptibility to gallstone formation by impairing gallbladder emptying function, disrupting biliary cholesterol metabolism, and enhancing intestinal cholesterol absorption in mice.

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Section: Introductionmentioning

confidence: 99%

The cholecystokinin‐1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice

Wang

Portincasa

Wang

2016

Eur J Clin Investigation

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Aminolactam, N-Aminoimidazolone, and N-Aminoimdazolidinone Peptide Mimics

St‐Cyr

García-Ramos

Doan

et al. 2017

Topics in Heterocyclic Chemistry

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Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking

Toumi-Maouche¹,

Maouche²,

Taïri-Kellou³

et al. 2008

J Mol Model

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Pyridopyrimidine-based analogues are among the most highly potent and selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) described to date. To better understand the structural and chemical features responsible for the recognition mechanism, and to explore the binding pocket of these compounds, we performed automated molecular docking using GOLD2.2 software on some derivatives with structural diversity, and propose a putative binding conformation for each compound. The docking protocol was guided by the key role of the Asn333 residue, as revealed by site directed mutagenesis studies. The results suggest two putative binding modes located in the same pocket. Both are characterized by interaction with the main residues revealed by experiment, Asn333 and Arg336, and differ in the spatial position of the Boc-Trp moiety of these compounds. Hydrophobic contacts with residues Thr117, Phe107, Ile352 and Ile329 are also in agreement with experimental data. Despite the poor correlation obtained between the estimated binding energies and the experimental activity, the proposed models allow us to suggest a plausible explanation of the observed binding data in accordance with chemical characteristics of the compounds, and also to explain the observed diastereoselectivity of this family of antagonists towards CCK1R. The most reasonable selected binding conformations could be the starting point for future studies. Figure Superimposition of the two putative binding conformations revealed by molecular docking for pyridopyrimidine-based CCK1 antagonists.

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Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands

Cited by 13 publications

References 86 publications

The cholecystokinin‐1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice

The cholecystokinin‐1 receptor antagonist devazepide increases cholesterol cholelithogenesis in mice

Aminolactam, N-Aminoimidazolone, and N-Aminoimdazolidinone Peptide Mimics

Exploring the binding pocket for pyridopyrimidine ligands at the CCK1 receptor by molecular docking

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