Cholecystokinin and gastrin antagonists

Freidinger, Roger

doi:10.1002/med.2610090303

Cited by 73 publications

(25 citation statements)

References 74 publications

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“…The first highly selective and potent non-peptidyl ligands developed and reported to work at CCK receptors were benzodiazepines (Freidinger, 1989). These have also been the most extensively studied in regard to mechanism of binding to CCK receptors.…”

Section: Molecular Basis Of Non-natural Ligand Bindingmentioning

confidence: 99%

“…These have also been the most extensively studied in regard to mechanism of binding to CCK receptors. It is notable that minor variations in the structures of these ligands were able to change their relative selectivities from CCK 1 to CCK 2 (Freidinger, 1989) and from antagonist to agonist at the CCK 1 receptor (Aquino et al, 1996). These data support the presence of binding pockets in these receptors that are related to each other, yet that have adequate differences to allow distinctive patterns of action.…”

Section: Molecular Basis Of Non-natural Ligand Bindingmentioning

confidence: 99%

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Structural basis of cholecystokinin receptor binding and regulation

Miller

Gao

2008

Pharmacology & Therapeutics

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Two structurally-related guanine nucleotide-binding protein-coupled receptors for two related peptides, cholecystokinin (CCK) and gastrin, have evolved to exhibit substantial diversity in specificity of ligand recognition, in their molecular basis of binding these ligands, and in their mechanisms of biochemical and cellular regulation. Consistent with this, the CCK 1 and CCK 2 receptors also play unique and distinct roles in physiology and pathophysiology. The paradigms for ligand recognition and receptor regulation and function are reviewed in this article, and should be broadly applicable to many members of this remarkable receptor superfamily. This degree of specialization is instructive and provides an encouraging basis for the diversity of potential drugs targeting these receptors and their actions that can be developed.

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Section: Molecular Basis Of Non-natural Ligand Bindingmentioning

confidence: 99%

Section: Molecular Basis Of Non-natural Ligand Bindingmentioning

confidence: 99%

Structural basis of cholecystokinin receptor binding and regulation

Miller

Gao

2008

Pharmacology & Therapeutics

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“…The tryptophan and aspartic acid within the C-terminal tetrapeptide of CCK are also key amino acids (16,17). The structure of several classes of CCK-AR antagonists and agonists contain structural elements that resemble tryptophan and aspartic acid side-chains, suggesting that all ligands may share determinants of the CCK-AR binding site (3,18).…”

mentioning

confidence: 99%

Arginine 336 and Asparagine 333 of the Human Cholecystokinin-A Receptor Binding Site Interact with the Penultimate Aspartic Acid and the C-terminal Amide of Cholecystokinin

Gigoux

Escrieut

Fehrentz

et al. 1999

Journal of Biological Chemistry

105

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“…Devazepide has been shown to be highly potent by several routes of administration, including oral, in a variety of functional assays such as gastric emptying and gall bladder contraction in a number of different species, and no agonistic activity has been observed. 73 It has also been demonstrated that devazepide crosses the blood-brain barrier efficiently. 134,135 Due to its high potency, selectivity and bioavailability, devazepide has been the reference CCK 1 receptor antagonist more widely used as pharmacological tool for the study of the physiological effects of CCK and its receptors.…”

Section: Cck 1 Receptor Antagonistsmentioning

confidence: 98%

“…Several reviews covering diverse aspects of CCK receptor agonists and antagonists have been published over the last years. [73][74][75][76][77][78][79][80][81][82][83] This article reviews the main advances in the development of CCK receptor antagonists, focusing mainly on those that have shown a greater pharmacological potential and those that could have a more promising therapeutic prospect.…”

Section: C C K R E C E P T O R a N T A G O N I S T Smentioning

confidence: 99%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

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Cholecystokinin and gastrin antagonists

Cited by 73 publications

References 74 publications

Structural basis of cholecystokinin receptor binding and regulation

Structural basis of cholecystokinin receptor binding and regulation

Arginine 336 and Asparagine 333 of the Human Cholecystokinin-A Receptor Binding Site Interact with the Penultimate Aspartic Acid and the C-terminal Amide of Cholecystokinin

Cholecystokinin antagonists: Pharmacological and therapeutic potential

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