FPL 14294: A novel CCK-8 agonist with potent intranasal anorectic activity in the rat

Simmons, Roy D.; Blosser, James C.; Rosamond, J.R.

doi:10.1016/0091-3057(94)90176-7

Cited by 26 publications

(12 citation statements)

References 33 publications

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“…Particular interest has rested on CCK-A selective agonist research showing potential for use as satiety or anorexic agents, by diminishing the meal duration and of the meal size [78]. These kind of agonists could also prevent gallbladder stasis on low fat diet as the activation of CCK-A receptors for the prevention of gallstones has also been demonstrated [80].…”

Section: The Cck-a Ligandsmentioning

confidence: 98%

Therapeutic and chemical developments of cholecystokinin receptor ligands

Tullio¹,

Delarge²,

Pirotte³

2000

Expert Opinion on Investigational Drugs

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Cholecystokinin (CCK) is an important 'brain-gut' hormone located both in the gastrointestinal (GI) system and in the CNS. At least two different G-coupled high affinity receptors have been identified: the CCK-A and the CCK-B receptors. Although the complex biological role of CCK is, as yet, not fully understood, its connection with many different physiological processes both at the GI level and at the CNS level is now well established. There is much potential for therapeutic use of CCK receptor ligands, however, clear investigations have yet to be completed. Several chemical families have been investigated over the last 20 years to find potent, subtype selective and stable CCK receptor agonists and antagonists. The main goal was to discover new therapeutic drugs acting on GI and/or on CNS diseases and also, to obtain powerful pharmacological tools that could permit a better understanding of the biological role of CCK. Despite promising results from investigations into medicinal chemistry of CCK receptor ligands, the therapeutical applications of these ligands still remains to be defined. This article reviews the main biological role of CCK, the therapeutic potential of CCK-A and CCK-B receptor agonists and antagonists and the common compounds from the different families of ligands.

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Section: The Cck-a Ligandsmentioning

confidence: 98%

Therapeutic and chemical developments of cholecystokinin receptor ligands

Tullio¹,

Delarge²,

Pirotte³

2000

Expert Opinion on Investigational Drugs

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“…Further modifications to CCK‐8 resulted in FPL14294 (also known as ARL142941 and ARR142941) (Hpa(SO3H)‐Met‐Gly‐Trp‐Met‐Asp‐(Me)Phe‐NH2) (Simmons et al. , 1994) and then the improved analogue ARR15849 (also known as ARL15849) (4‐hydroxyphenylacetyl(SO 3 H)‐Nle‐Gly‐Trp‐Nle‐(Me)Asp‐Phe‐NH 2 ) (Pierson et al.…”

Section: Cck1 Receptor Peptide Analogues Of Cckmentioning

confidence: 99%

Therapeutic potential for novel drugs targeting the type 1 cholecystokinin receptor

Cawston

Miller

2010

British J Pharmacology

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Cholecystokinin (CCK) is a physiologically important gastrointestinal and neuronal peptide hormone, with roles in stimulating gallbladder contraction, pancreatic secretion, gastrointestinal motility and satiety. CCK exerts its effects via interactions with two structurally related class I guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), the CCK1 receptor and the CCK2 receptor. Here, we focus on the CCK1 receptor, with particular relevance to the broad spectrum of signalling initiated by activation with the natural full agonist peptide ligand, CCK. Distinct ligand-binding pockets have been defined for the natural peptide ligand and for some non-peptidyl small molecule ligands. While many CCK1 receptor ligands have been developed and have had their pharmacology well described, their clinical potential has not yet been fully explored. The case is built for the potential importance of developing more selective partial agonists and allosteric modulators of this receptor that could have important roles in the treatment of common clinical syndromes. (2010) , 90-kDa ribosomal S6 protein kinase; PI3K, class I phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; SAR, drug structure-activity relationship; Shc, Src homology/ collagen related; SOS, Drosophila homolog, Son of Sevenless British Journal of PharmacologyThe main purpose of this report is to explore the therapeutic potential of highly selective partial agonists and allosteric modulators of the type 1 cholecystokinin (CCK) receptor (CCK1 receptor). To more fully appreciate this selective role, the normal physiology and pathophysiology of this receptor and of its natural, full agonist ligand, CCK, must first be reviewed.Cholecystokinin is one of the earliest gastrointestinal hormones to be discovered, identified more than 90 years ago based on its ability to stimulate gallbladder contraction (Ivy and Oldberg, 1928). It was soon recognized to be identical to the factor responsible for stimulating pancreatic exocrine secretion (Harper and Raper, 1943). This hormone has subsequently been shown to have effects on enteric smooth muscle and on nerves at various locations in the peripheral and central nervous system (Rehfeld, 2004). One of its most important neural effects is post-cibal satiety (Kissileff et al.,

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“…To do this, we used much of the data which has been previously reported and attempted to systematically assemble it into a single peptide agonist with the desired pharmacokinetic profile.  Activity is restored to non-sulfated CCK-4 when Met31 is replaced with a Lys(Tac) residue [2]  Hexapeptide analogs retain potency when both Met28 and Met31 are replaced with norleucine [3]  N-methyl-Phenylalanine enhances metabolic stability [4]  N-terminal pGlu-Gln enhances metabolic stability [5] The literature modifications were systematically incorporated, resulting in peptide 34 (Table 1) which had the desired potency, selectivity, food intake reduction and a solubility > 150 mg/mL. While endogenous CCK-8 lacks the selectivity duration of action and solubility to be used as an effective tool compound in combination studies, the introduction of modifications to the peptide sequence gleaned from the literature enabled us to generate a suitable molecule.…”

Section: Resultsmentioning

confidence: 99%