Selective CCK-A Receptor Agonists Research Articles

Serotonin-3 receptors in gastric mechanisms of cholecystokinin-induced satiety

our understanding of the controls of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually

Postprandial neuronal activation in the nucleus of the solitary tract is partly mediated by CCK-A receptors.

CCK-A receptors and neurons of the nucleus of the solitary tract (NTS) are involved in the regulation of food intake, and in rats, there is evidence for involvement of an intestinal vagal afferent pathway. Studies investigating the role of CCK-A receptors in activation of NTS neurons using highly selective CCK-A receptor agonists and antagonists have yielded conflicting data. In the present study, we investigated CCK-induced and postprandial activation of NTS neurons, together with food intake studies, in CCK-A receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats. Activated NTS neurons were detected using immunohistological staining for c-Fos protein. Exogenous CCK increased the number of c-Fos protein-positive cells in the NTS of Sprague-Dawley and CCK-A receptor-intact Long-Evans Tokushima Otsuka (LETO) rats but had no effect in CCK-A receptor-deficient OLETF rats. Food intake-induced c-Fos protein expression in NTS neurons was significantly reduced in CCK-A receptor-deficient OLETF rats compared with Sprague-Dawley or LETO rats. Postprandial c-Fos protein expression in the NTS was also significantly decreased after pretreatment with the CCK-A receptor antagonist MK329 after both short- and long-term fasting periods. Exogenous CCK decreased cumulative food intake in Sprague-Dawley and LETO rats but not in OLETF rats. These data demonstrate that CCK-A receptors are involved in the CCK- and food-induced c-Fos protein expression in the NTS. Taken together with the results of the food intake studies, this suggests that activation of CCK-A receptors is involved in the postprandial activation of NTS neurons and in the regulation of food intake.

Synthesis and biological activities of peptidomimetic analogues of compound A71623, a potent and selective CCK-A receptor agonist

The involvement of cholecystokinin receptors in the phenomenon of satiety has been the impetus for significant research efforts, leading to the design and synthesis of CCK-A selective agonists for the possible treatment of obesity. The Abbott laboratories have described a novel series of pseudotetrapeptides represented by compound A71623, a highly potent and selective peripheral receptor agonist, but possessing very poor bioavailability. Starting from the structural requirements of this series of compounds, a peptidomimetic study was investigated, especially focusing on the N-terminal part of A71623. Using standard coupling methods, introduction of unnatural aromatic amino acids bearing a 2-carboxyethyl side chain on their α-amino group, along with backbone length modulation, afforded selective analogues, presenting a highly modified peptidic backbone. From our two lead compounds, further optimization is under development, tending towards nonpeptidic structures.

Further evidence on the role of central cholecystokinin-B (CCK-B) receptors in anxiety: A study with GV 1500013 a novel CCK-B antagonist

Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) and emotional stress (ES) induce stimulation of colonic motility in rats, an effect blocked by i.c.v. injection of CCK-8s. This study examined in rats the contribution of the central nucleus of the amygdala (CA) in the blocking effect of CCK-8s on ES and CRF-induced colonic hypermotility. CRF (500 ng/kg, i.c.v.) induced a 73.5% increase in colonic spike burst frequency. Bilateral infusions of 1, 5, 10 and 20 ng/kg of CCK-8s in the CA region 10 min prior to CRF i.c.v. injection reduced, in a dose related manner, the CRF-induced stimulation of colonic motility. A 109% increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks (ES). CCK-8s and A-71623, a selective CCK-A receptor agonist, (10, 25 and 50 ng/kg) infused bilaterally into the CA, 30 min before ES, significantly reduced this stimulatory effect, while CCK-4 and A-63387, a selective CCK-B receptor agonist (10, 25 and 50 ng/kg), had no effect on such a response. CA lesions by ibotenic acid did not affect ES-induced increase in colonic spike activity. However, CCK-8s (50 ng/kg) microinfused into CA lesioned rats was unable to block the ES-induced stimulation of colonic motility, while CCK-8s i.c.v. injected (100 ng/kg) is still active on the colonic response to ES. These results suggest that CA is a site of interaction of CCK-8s with CRF to block the colonic response to stress and that these effects involve the CCK-A receptor subtype. Furthermore, CA is not a brain structure involved in stress-induced stimulation of colonic motility.

Cholecystokinin blockade of emotional stress- and CRF-induced colonic motor alterations in rats: role of the amygdala

Intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) and emotional stress (ES) induce stimulation of colonic motility in rats, an effect blocked by i.c.v. injection of CCK-8s. This study examined in rats the contribution of the central nucleus of the amygdala (CA) in the blocking effect of CCK-8s on ES and CRF-induced colonic hypermotility. CRF (500 ng/kg, i.c.v.) induced a 73.5% increase in colonic spike burst frequency. Bilateral infusions of 1, 5, 10 and 20 ng/kg of CCK-8s in the CA region 10 min prior to CRF i.c.v. injection reduced, in a dose related manner, the CRF-induced stimulation of colonic motility. A 109% increase in colonic spike burst frequency was observed in rats placed in a test cage in which they had previously received electric footshocks (ES). CCK-8s and A-71623, a selective CCK-A receptor agonist, (10, 25 and 50 ng/kg) infused bilaterally into the CA, 30 min before ES, significantly reduced this stimulatory effect, while CCK-4 and A-63387, a selective CCK-B receptor agonist (10, 25 and 50 ng/kg), had no effect on such a response. CA lesions by ibotenic acid did not affect ES-induced increase in colonic spike activity. However, CCK-8s (50 ng/kg) microinfused into CA lesioned rats was unable to block the ES-induced stimulation of colonic motility, while CCK-8s i.c.v. injected (100 ng/kg) is still active on the colonic response to ES. These results suggest that CA is a site of interaction of CCK-8s with CRF to block the colonic response to stress and that these effects involve the CCK-A receptor subtype. Furthermore, CA is not a brain structure involved in stress-induced stimulation of colonic motility.

Intraventricular CCK-8 reduces single meal size in the baboon by interaction with type-A CCK receptors.

Intraventricular cholecystokinin COOH-terminal octapeptide (CCK-8) decreases meal size in the meal-trained baboon. In the present study, we tested whether this action is mediated by CCK-A receptors, CCK-B receptors, or both. Intraventricular administration of the selective CCK-A receptor agonist A71623 at 1 and 10 nmol/kg suppressed 30-min meal size 69 +/- 22% and 75 +/- 7%, respectively. Additionally, intraventricular A71623 was equipotent to CCK-8 at 1 nmol/kg (% suppression of meal by CCK = 59 +/- 17). However, intraventricular administration of the CCK-B receptor agonist A63387 at 10 nmol/kg had no effect on 30-min meal size (% suppression = 18 +/- 29). Intravenous administration of 10 nmol/kg A71623 did not result in an alteration of meal size, but prandial plasma insulin and glucose responses were delayed and blunted. Basal plasma insulin levels doubled after intravenous administration of A71623. Both behavioral and metabolic responses to A71623 in the baboon are virtually identical to those we have previously observed after CCK-8 treatment. Thus we conclude that the predominant receptor population with which intraventricular CCK-8 interacts are type-A CCK receptors that are accessible to the ventricular system of the baboon.

A-71623, a selective CCK-A receptor agonist, suppresses food intake in the mouse, dog, and monkey

The anorectic actions of cholecystokinin (CCK)-8 and of a selective CCK-A agonist, A-71623, were examined in CD1 mice, beagle dogs, and cynomolgous monkeys. A-71623 suppressed intakes in all species tested, and the effects were blocked by a selective CCK-A antagonist, A-70104. In the dog only, CCK-8 was more potent on a molar basis compared to A-71623, although the effects of both CCK agonists were more short-lived in the dog compared to the other species tested. Our results support other evidence suggesting that the anorectic actions of exogenous application of CCK-8 in these species are mediated via stimulation of the CCK-A receptor subtype.

Behavioral effects of A71623, a highly selective CCK-A agonist tetrapeptide.

We studied the behavioral effects of a novel cholecystokinin tetrapeptide (CCK-4) analogue, A71623, with full agonist activity and high affinity and selectivity for the CCK-A receptor subtype relative to the CCK-B receptor. In tests for anorectic activity, A71623 was found to suppress 60-min intakes of a liquid diet in both deprived and sated rats, and the effects were blocked by a selective CCK-A antagonist, A70104. Compared with CCK-8, A71623 was found to have improved potency and duration of action; the most potent route of administration was intraperitoneal. A71623 also suppressed the intake of a liquid diet and a 0.2 M sucrose solution in lean and obese Zucker rats. In daily injection studies, the anorectic activity of CCK-8 diminished rapidly, whereas the suppressant effects of A71623 on food intakes and body weight gains persisted throughout the 11-day treatment period. Finally, A71623 reduced the spontaneous locomotor activity of rats at doses above those required to suppress intakes. These studies are the first to describe the behavioral effects of a potent and highly selective CCK-A receptor agonist.

Effects of selective CCK receptor agonists on food intake after central or peripheral administration in rats

In this paper we report the effects of peripheral (intraperitoneal, i.p.) and central (intracerebroventricular, i.c.v.) injection of selective cholecystokinin (CCK) receptor agonists on food intake in the rat. Stimulation of peripheral and central CCK-A receptors by the selective CCK-A receptor agonist A-71623 suppressed intakes of a liquid diet in both deprived and sated rats. In contrast, i.c.v., but not i.p., injections of the selective CCK-B receptor agonist A-63387, reduced food intakes, although on a molar basis the effect was much less than that seen with A-71623. Although these results stress the relative importance of the CCK-A receptor in the effects of exogenous CCK-8 administration on feeding, stimulation of the CCK-B receptor may still be involved in the control of feeding following the endogenous release of CCK.

Boc-CCK-4 derivatives containing side-chain ureas as potent and selective CCK-A receptor agonists

Novel Boc-CCK-4 derivatives were communicated recently as having high potency and selectivity for the CCK-A receptor (Shiosaki et al. J. Med. Chem. 1990, 33, 2950-2952). While Boc-CCK-4 binds selectively to the CCK-B receptor, replacement of the methionine with an N epsilon-substituted lysine dramatically reversed receptor selectivity, leading to the development of this novel series of tetrapeptides. A detailed structure-activity analysis of a series of urea-substituted tetrapeptides, represented by the general structure Boc-Trp-Lys(N epsilon-CO-NHR)-Asp-Phe-NH2, revealed that a number of substituted phenyl, naphthyl, and aliphatic urea residues in the lysine side chain yielded potent and selective CCK-A ligands. These tetrapeptides elicit full agonist responses in stimulating pancreatic amylase release that are effectively blocked by a selective CCK-A receptor antagonist. Conversion of the urea to a thiourea significantly reduced CCK-A binding potency as did replacement of the lysine with the homologous ornithine or homolysine. Tetrapeptides that were partial agonists (less than 80% efficacy) in phosphoinositide (PI) hydrolysis relative to CCK-8 did not exhibit high-dose inhibition of amylase secretion in guinea pig acini.

Development of CCK-tetrapeptide analogs as potent and selective CCK-A receptor agonists

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDevelopment of CCK-tetrapeptide analogs as potent and selective CCK-A receptor agonistsKazumi Shiosaki, Chun Wel Lin, Hana Kopecka, Richard Craig, Frank L. Wagenaar, Bruce Bianchi, Thomas Miller, David Witte, and Alex M. NadzanCite this: J. Med. Chem. 1990, 33, 11, 2950–2952Publication Date (Print):November 1, 1990Publication History Published online1 May 2002Published inissue 1 November 1990https://doi.org/10.1021/jm00173a006RIGHTS & PERMISSIONSArticle Views112Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (442 KB) Get e-Alerts Get e-Alerts