Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

Holladay, Mark W.; Bennett, Michael J.; Tufano, Michael D.; Lin, Chun–Wei; Asin, Karen E.; Witte, David G.; Miller, Thomas R.; Bianchi, Bruce R.; Nikkel, Arthur L.; Bednarz, L.

doi:10.1021/jm00094a001

Cited by 23 publications

(30 citation statements)

References 12 publications

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“…Starting from pentagastrin, a four amino acid peptide, compounds have shown interesting affinity and selectivity for CCK-BR and several structural modulations led to the discovery of various potent CCK-BR agonists, such as A-72962 (34) [106] and BC-264 (Figure 7, 35) [107]. Cyclic peptides were also prepared based on a model of CCK-8.…”

Section: The Cck-b Ligandsmentioning

confidence: 99%

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-b Ligandsmentioning

confidence: 99%

Therapeutic and chemical developments of cholecystokinin receptor ligands

Tullio¹,

Delarge²,

Pirotte³

2000

Expert Opinion on Investigational Drugs

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“…The two dis sociation constants calculated for A-71,378, a heptapeptide derivative of CCK-8s, suggest that this agonist bound to a major population of CCKA-like receptors and to a minor popu lation ofCCKe-like receptors [8]. The calcu lated binding parameters (see table 1) trans late into a 3:1 density ratio of these receptor subtypes in the porcine gastric mucosa.…”

Section: Discussionmentioning

confidence: 91%

“…3, table 2). In contrast, the CCKB receptor selective ana logue A-72,962 [8] was only a weak stimulus of porcine pepsinogen secretion, with a threshold concentration as high as 10 pmol l-'. Among naturally occurring agonists, the amphibian decapeptide caerulein [25] was similarly efficacious and potent as CCK-8s, whereas gastrin-17-1 did not stimulate pep sinogen secretion within the tested concentra tion range of up to 10 pmol 1_1 (fig.…”

Section: Determination O F Pepsinogen Secretion and Control Oj'ldh Rementioning

confidence: 81%

“…Our strategy was to establish initially by radioli gand binding experiments the presence of CCKa and CCKB receptors in porcine gastric mucosa, and then to examine which of these mucosal receptors triggers pepsinogen secre tion from isolated porcine chief cells. For pharmacological analysis, we took advantage of the fact that the CCKA and CCKB receptors share high affinity for the endogenous agonist CCK octapeptide (CCK-8s), but can be distin guished by the CCKB receptor selective en dogenous peptide hormone, gastrin-17-1 [1], CCKa and CCKB receptors are also distin guished by the subtype-selective heptapeptide agonists A-71,378 and A-72,962, respectively [7,8] or by the subtype-selective antagonists L-364.718 and L-365,260 [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of CCK<sub>A</sub> Receptor Mediated Pepsinogen Secretion in Porcine Chief Cells

Meyer

Beinborn²,

Sewing³

1996

Pharmacology

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Cholecystokinin octapeptide (CCK-8s) is an endogenous stimulus of gastric pepsinogen secretion. Previous studies with isolated guinea pig chief cells indicated that this process is mediated through the CCK_A receptor subtype, with an additional contribution from CCK_B receptors. For comparison, we examined the mechanism of CCK-8s stimulated pepsinogen secretion in a larger nonrodent species, using highly enriched porcine chief cells as a functional in vitro model. Porcine chief cells responded weakly to stimulation by CCK-8s alone, but the efficacy was markedly enhanced in the presence of 10 µmol l^–1 forskolin. Under these conditions, pepsinogen secretion was potently stimulated by CCK-8s and the CCKa receptor selective heptapeptide, A-71,378 (EC50 = 4.7 and 33 nmol H), but not by CCK_B receptor selective agonists. The prototype CCKa receptor selective antagonist L-364,718 blocked pepsinogen secretion with ∼2,000-fold higher affinity than the CCK_B receptor selective analogue, L-365,260. This functional profile was consistent with the affinity rank order of all tested compounds at CCK_A-receptor-like [¹²⁵I]-BH-CCK-8s binding sites in the porcine gastric mucosa. Comparison with cloned CCK_A receptors from other species revealed that the receptors mediating pepsinogen secretion in the pig have similar pharmacology, possibly with slight differences in agonist potencies. In contrast to the guinea pig, porcine CCK_B receptors appear to have no direct role in pepsinogen secretion.

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“…Only few compounds have been reported to be CCK1 selective agonists, most of them are tetrapeptides, such as A-71378 [des-NH 2 -Tyr(SO 3 H)-Nle-Gly-Trp-Nle-(NMe)Asp-Phe-NH 2 ], which contains an (NMe)Asp residue that is critical for CCK1 receptor selectivity [46]. The other series is based on tetrapeptides containing a substituted Lys residue, such as A-71623 [BOC-Trp-Lys(o-toluylaminocarbonyl)-Asp-(NMe)-Phe-NH2] and A-70874 [Boc-Trp-Lys(p-hydroxycinnamoyl)-Asp-(NMe)Phe-NH2].…”

Section: Design Of Selective Peptide Agonists For Cck1 Receptors (Tabmentioning

confidence: 99%

Pharmacology of CCKRs and SAR Studies of Peptidic Analog Ligands

Noble

2007

CTMC

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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 (CCK(8)) 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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Synthesis and biological activity of CCK heptapeptide analogs. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo

Cited by 23 publications

References 12 publications

Therapeutic and chemical developments of cholecystokinin receptor ligands

Therapeutic and chemical developments of cholecystokinin receptor ligands

Characterization of CCK<sub>A</sub> Receptor Mediated Pepsinogen Secretion in Porcine Chief Cells

Pharmacology of CCKRs and SAR Studies of Peptidic Analog Ligands

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