Current Topics in Medicinal Chemistry

ISSN: 1568-0266

Current Topics in Medicinal Chemistry
Volume 7, Number 12, 2007

Contents

Cholecystokinin Receptors as Targets in Medicinal Chemistry
Guest Editor: Daniel Fourmy


Editorial Pp. 1153


The Biology of Cholecystokinin and Gastrin Peptides Pp. 1154-1165
Jens F. Rehfeld, Lennart Friis-Hansen, Jens P. Goetze and Thomas v. O. Hansen
[Abstract]


Biochemical and Cell Biological Mechanisms of Cholecystokinin Receptor Regulation Pp. 1166-1172
Laurence J. Miller, Maoqing Dong, Kaleeckal G. Harikumar and Cayle S. Lisenbee
[Abstract]


Pharmacology of CCKRs and SAR Studies of Peptidic Analog Ligands Pp. 1173-1179
Florence Noble
[Abstract]


Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands Pp. 1180-1194
M. Teresa García-López, Rosario González-Muñiz, Mercedes Martín-Martínez and Rosario Herranz
[Abstract]


Strategies for the Design of Non-peptide CCK₂ Receptor Agonist and Antagonist Ligands Pp. 1195-1204
S. Barret Kalindjian and Iain M. McDonald
[Abstract]


Cholecystokinin 1(A) Receptor Polymorphisms Pp. 1205-1210
Kyoko Miyasaka, Soichi Takiguchi and Akihiro Funakoshi
[Abstract]


Role of CCK/Gastrin Receptors in Gastrointestinal/Metabolic Diseases and Results of Human Studies Using Gastrin/CCK Receptor Agonists/Antagonists in these Diseases Pp. 1211-1231
Marc J. Berna and Robert T. Jensen
[Abstract]


CCK Receptors and Cancer Pp. 1232-1236
Graham S. Baldwin and Arthur Shulkes
[Abstract]


Targeting CCK Receptors in Human Cancers Pp. 1239-1242
Jean Claude Reubi
[Abstract]


Validated Ligand Binding Sites in CCK Receptors. Next Step: Computer-Aided Design of Novel CCK Ligands Pp. 1243-1247
Irina G. Tikhonova, Esther Marco, Elodie Lahlou-Archer, Ingrid Langer, Magali Foucaud, Bernard Maigret and Daniel Fourmy
[Abstract]


Molecule of Month




Abstracts

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Editorial

Cholecystokinin (CCK) and gastrin are among the first gastrointestinal hormones discovered. Since the first sequencing of these regulatory peptides in 1964 and 1968, a huge amount of basic and translational research work has been carried. Due to their wide tissue distribution in both the central nervous system and peripheral organs and to the number of biological processes which they regulate, CCK and gastrin receptors are undoubtedly important candidate targets in medicine. These receptors are still the subject of intensive research today.

In this special issue of Current Topics in Medicinal Chemistry are gathered 10 articles related to cholecystokinin and gastrin receptors written by world-wide acknowledged experts in the field.

In a first article, Jens Rehfeld and colleagues draw a picture of the available knowledge related to cellular synthesis, secretion and processing of cholecystokinin and gastrin peptides as well as to major physiological effects of the two peptides.

In a second article Larry Miller and collegues describe the biochemical and cell biological mechanisms of cholecystokinin receptor regulation. These include receptor phosphorylation/dephosphorylation by specific enzymes, internalization/ intracellular trafficking and oligomerisation.

In a third article, Florence Noble reports major data on the design of peptidic ligands specific for the CCK receptors and some pharmacological properties of these ligands, with a special focusing on the central nervous system.

In the following two articles, Rosario Herranz and Barrett Kalindjian and colleagues review the last five literature years of medicinal chemistry of non peptide ligands of CCK1R and CCK2R.

In a sixth article, Kyoko Miyasaka and colleagues describe available data on CCK1R polymorphism and its patho-physiological relevance in humans.

In a seventh article, Marc Berna and Robert Jensen report in detail the established and possible roles of CCK1 and CCK2 receptors in gastrointestinal and metabolic diseases and discuss available results from human agonist/antagonist studies.

In the following paper, Graham Baldwin reviews the most recent data in relation to CCK receptors and cancer and possible therapeutic implications, which has been a field of intensive investigations.

In another article, Jean-Claude Reubi focuses his report on expression of CCK receptors in certain neuroendocrine tumours and on the promising use of CCK-related radiolabelled ligands to identify and cure these cancers.

In the last article, Irina Tikhinova and colleagues, introduce and develop the concept of target-structure based design of ligands which could be applied to CCK receptors on the basis of data from CCK receptor binding site studies and further to other G-protein coupled receptors for which no satisfactory ligand is available.

I wish to express my thanks to all contributors of this special issue which hopefully will be an helpful source of information for investigators in this field as well as in the wide field of G protein coupled receptors.


Daniel Fourmy
Research Director
INSERM, Toulouse
France


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The Biology of Cholecystokinin and Gastrin Peptides
Jens F. Rehfeld, Lennart Friis-Hansen, Jens P. Goetze and Thomas v. O. Hansen

Cholecystokinin (CCK) and gastrin together constitute a family of homologous peptide hormones, which are both physiological ligands for the gastrin/CCK-B receptor, whereas the CCK-A receptor binds only sulfated CCK-peptides. CCK peptides are mainly produced in small intestinal endocrine I-cells and in cerebral neurons. CCK peptides regulate pancreatic enzyme secretion and growth, gallbladder contraction, intestinal motility, satiety and inhibit gastric acid secretion. Moreover, they are potent neurotransmitters in the brain and the periphery. CCK peptides are derived from proCCK and have the bioactive heptasequence -Tyr(SO₄)-Met-Gly-Trp-Met-Asp-Phe-NH₂ as their C-terminus. The dominant forms in plasma are CCK-58, CCK-33, CCK-22 and CCK-8, whereas CCK-8 is the major transmitterform. Due to scarcity of specific assays, knowledge about CCK in disease is still limited. Gastrin peptides are mainly synthetized in antroduodenal G-cells, from where they are released to blood to regulate gastric acid secretion and mucosal growth. Small amounts are synthetized further down the intestinal tract, in the foetal pancreas, in a few cerebral and peripheral neurons, in the pituitary gland and in spermatozoes. Gastrin peptides are derived from progastrin and all have the C-terminal bioactive hexasequence -Tyr (SO₄)-Gly-Trp-Met-Asp-Phe-NH₂. The major gastrin forms in tissue and plasma are gastrin-34 and gastrin-17, but also gastrin-71, -14 and -6 have been identified. Gastrin peptides are secreted in excessive amounts from gastrinomas and are expressed at lower levels in bronchogenic, colorectal, gastric, ovarian and pancreatic cancers. A carcinogenetic significance of gastrin peptides remains, however, to be proven.


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Biochemical and Cell Biological Mechanisms of Cholecystokinin Receptor Regulation
Laurence J. Miller, Maoqing Dong, Kaleeckal G. Harikumar and Cayle S. Lisenbee

Regulation of the cholecystokinin receptor is accomplished by biochemical and cell biological mechanisms. The major mechanism for biochemical regulation involves phosphorylation of serine and threonine residues within the receptor’s intracellular third loop and carboxyl-terminal tail. This form of rapid desensitization is achieved by protein kinase C, a kinase activated in the normal signaling cascade of this Gq-coupled receptor, and/or a member of the G protein-coupled receptor kinase family that recognizes the active conformation of the receptor. Conversely, a type 2A serine protein phosphatase has been shown to selectively act on this receptor in an agonist-regulated manner, resulting in receptor dephosphorylation and resensitization. Cell biological mechanisms for desensitization involve the net removal of receptors from exposure to circulating hormone via insulation within a specialized plasma membrane domain or internalization into the cell within endocytic compartments. Internalization has been shown to occur by both clathrin-dependent and clathrin-independent mechanisms, the latter believed to represent potocytosis in caveolae, that lead to recycling of receptors to the plasma membrane for resensitization or shuttling of receptors to lysosomes for degratory down-regulation. Interestingly, receptor phosphorylation has been shown to affect intracellular domain accessibility and receptor trafficking, although the specific proteins regulating this have not yet been identified. The cholecystokinin receptor can exist in the plasma membrane as oligomeric superstructures, namely as homomers with themselves or as heteromers with closely related class I G protein-coupled receptors. Agonist occupation results in oligomer dissociation, but the functional significance of this observation has yet to be defined.


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Pharmacology of CCKRs and SAR Studies of Peptidic Analog Ligands
Florence Noble

Cholecystokinin (CCK) is a peptide originally discovered in the gastrointestinal tract but also found in high density in the mammalian brain. The C-terminal sulphated octapeptide fragment of cholecystokinin (CCK₈) constitutes one of the major neuropeptides in the brain. CCK8, interacting with nanomolar affinities with two different receptors designated CCK1 and CCK2, has been shown to be involved in numerous physiological functions and is involved in the modulation/control of multiple central functions. In particular, CCK is involved in the neurobiology of anxiety, depression, psychosis, cognition, nociception and feeding behavior. The functional role of CCK has been facilitated thanks to the development of potent and selective CCK receptor antagonists and agonists. In this review, the strategies followed to design peptidic analog ligands will be reported, as the pharmacology of CCK receptors.


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Strategies for Design of Non Peptide CCK1R Agonist/Antagonist Ligands
M. Teresa García-López, Rosario González-Muñiz, Mercedes Martín-Martínez and Rosario Herranz

This review mainly covers last five year literature on CCK1R agonists and antagonists. These CCK1R ligands have been found following the two usual and complementary strategies for drug discovery: rational design based on structure activity relationships on the CCK-7 and CCK-4 peptide sequences of the endogenous ligands and random screening of diverse compounds, followed by hit optimization. The first group includes: chimeric bifunctional opioid/CCK peptides, designed as opioid agonists with balanced CCK1R/CCK2R antagonist activity for the treatment of neuropathic pain, antagonist and agonist dipeptoids, and 1,3-dioxoperhydropyrido[1,2-c]pyrimidine- and anthranilic acid-based antagonists. Among the ligands derived from random screening, a few new 1,4-benzodiazepine-, 1,5-benzodiazepine-, and five member ring heterocycle-based CCK1R ligands have been reported. Finally, taking into account the importance of receptor mapping studies for ligand optimization and future precise de novo receptor structure-based design of new selective and more effective ligands, the most significant conclusions of these studies have also been reviewed.


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Strategies for the Design of Non-peptide CCK₂ Receptor Agonist and Antagonist Ligands
S. Barret Kalindjian and Iain M. McDonald

There has been an effort towards the design and preparation of non-peptide antagonists of the CCK₂ receptor going back for over fifteen years. However, as no obvious unmet medical need for this type of molecule has emerged, the interest has somewhat declined. A number of comprehensive reviews have been written where much of the early work is described and so this article focuses on the information generated in the last five years. It is to be hoped that the area will regain some impetus following the recent disclosure of clinical trial data demonstrating the possible utility of a CCK₂ antagonist in pancreatic cancer.

When considering non-peptide agonists for the CCK₂ receptor, traditionally, much less work has been reported in the area. However, recent suggestions of possible clinical utility in the treatment of diabetes, functionally different subtypes of the receptor and molecular models of receptor-ligand interactions should act as a spur for work towards potent small molecule ligands.


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Cholecystokinin 1(A) Receptor Polymorphisms
Kyoko Miyasaka, Soichi Takiguchi and Akihiro Funakoshi

Since the isolation and sequencing of cholecystokinin (CCK), considerable advances have been made in understanding the roles played by this peptide as a hormone and as a neuropeptide. CCK-1(A) and 2(B) receptor (R) cDNAs have been cloned; shortly thereafter, the naturally occurring CCK-1R gene-deficient rat (the Otsuka Long-Evans Tokushima Fatty (OLETF) rat) was discovered. This strain develops adult-onset diabetes with obesity, and has a 6847 base-pair deletion of the CCK-1R gene in which the promoter lesion and the first two exons are missing. At the same time, the genomic structures of CCK-1R in rats, mice, and humans were clarified. The CCK-1R gene consists of five exons interrupted by four introns. It has been determined that there is species- and tissue-specific CCK receptor heterogeneity of expression; in particular, there is evidence that the human pancreas does not express CCK-1R, while the pancreas in rodents primarily expresses CCK-1R. Although CCK-1R polymorphisms with amino acid changes such as 21Gly to Arg, 71 Arg to Gly, and 364 Val to Ile were discovered in subjects with obesity and diabetes mellitus, these changes occur sporadically. We identified two sequence changes, a G to T change in nucleotide –128, and an A to G change in nucleotide –81, in the promoter region of the CCK-1R gene. This polymorphism is considered to be a single nucleotide polymorphism (SNP) related to weight control difficulties in obese subjects as well as to psychiatric disorders. The precise molecular mechanisms of this polymorphism remain to be clarified.


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Role of CCK/Gastrin Receptors in Gastrointestinal/Metabolic Diseases and Results of Human Studies Using Gastrin/CCK Receptor Agonists/Antagonists in these Diseases
Marc J. Berna and Robert T. Jensen

In this paper, the estabished and possible roles of CCK1 and CCK2 receptors in gastrointestinal (GI) and metabolic diseases are reviewed and available results from human agonist/antagonist studies are discussed. While there is evidence for the involvement of CCK1R in numerous diseases including pancreatic disorders, motility disorders, tumor growth, regulation of satiety and a number of CCK-deficient states, the role of CCK1R in these conditions is not clearly defined. There are encouraging data from several clinical studies of CCK1R antagonists in some of these conditions, but their role as therapeutic agents remains unclear. The role of CCK2R in physiological (atrophic gastritis, pernicious anemia) and pathological (Zollinger-Ellison syndrome) hypergastrinemic states, its effects on the gastric mucosa (ECL cell hyperplasia, carcinoids, parietal cell mass) and its role in acid-peptic disorders are clearly defined. Furthermore, recent studies point to a possible role for CCK2R in a number of GI malignancies. Current data from human studies of CCK2R antagonists are presented and their potential role in the treatment of these conditions reviewed. Furthermore, the role of CCK2 receptors as targets for medical imaging is discussed.


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CCK Receptors and Cancer
Graham S. Baldwin and Arthur Shulkes

Over the past 20 years there has been considerable interest in the role of CCK receptors in gastrointestinal cancer. Initial excitement over reports of the detection by PCR of CCK-1 and CCK-2 receptor mRNA in a wide range of gastrointestinal tumours has been tempered by the realisation that the presence of receptor binding sites is much more restricted. The current consensus is that expression of CCK-1 and -2 receptor proteins is common only in tumours of neural or neuroendocrine origin. A striking example of this general rule has been provided by the detection of CCK-2 receptors by receptor autoradiography in more than 90% of medullary thyroid carcinomas. Despite the absence of CCK receptors from many gastrointestinal adenocarcinomas, evidence from animal models and from tumour cell lines in vitro suggests that the CCK-2 receptor may contribute to the development of esophageal and gastric adenocarcinomas, and further experimental work in these areas is clearly warranted. Promising therapeutic approaches include the development of radiolabelled gastrin/CCK derivatives for use in tumour imaging, and the use of appropriate selective antagonists for treatment of those tumour subtypes likely to express CCK receptors.


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Targeting CCK Receptors in Human Cancers
Jean Claude Reubi

Gut hormone receptors can be over-expressed in several human cancers and represent the basis for receptor-targeted tumor imaging and therapy. A promising receptor for such clinical applications is the cholecystokinin receptor. Cholecystokinin receptors are expressed in numerous neuroendocrine tumors, in particular medullary thyroid carcinomas and neuroendocrine gut tumors, as well as in stromal tumors. Moreover, several radiolabeled CCK or gastrin analogs have been developed allowing to detect these tumors and their metastases in patients using in vivo cholecystokinin receptor scintigraphy, proving the feasibility of targeting CCK receptors in human tumors in vivo.


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Validated Ligand Binding Sites in CCK Receptors. Next Step: Computer-Aided Design of Novel CCK Ligands
Irina G. Tikhonova, Esther Marco, Elodie Lahlou-Archer, Ingrid Langer, Magali Foucaud, Bernard Maigret and Daniel Fourmy

Computer-aided drug design becomes an important part of G-protein coupled receptors (GPCR) drug discovery process that is applied for improving the efficiency of derivation and optimization of novel ligands. It represents the combination of methods that use structural information of a receptor binding site of known ligands to design new ligands. In this report, we give a brief description of ligand binding sites in cholecystokinin and gastrin receptors (CCK1R and CCK2R) which were delineated using experimental and computational methods, and then, we show how the validated ligand binding sites can be used to design and improve novel ligands. The translation of the knowledge of ligand-binding sites of different GPCRs to computer-aided design of novel ligands is summarized.