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      • Record: found
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      Biological Effects of Newly Synthesized Cholecystokinin Analogs

      ,

      Hormone Research in Paediatrics

      S. Karger AG

      Cholecystokinin analogs, Endocrine pancreas, Ileum, Brain

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          Abstract

          Cholecystokinin (CCK) is a gut hormone that regulates pancreatic endocrine functions via CCK<sub>A</sub> receptors. CCK<sub>4</sub> (Trp-Met-Asp-Phe-NH<sub>2</sub>) has an insulinotropic effect, but is 1,000-fold less potent than CCK<sub>8</sub> in rodents. The in vitro potencies with respect to binding, the biological effects and the selectivity of newly synthesized CCK<sub>4</sub> analogs constructed by computer modelling experiments were investigated in vitro in rat pancreas and brain, INS-1 cells, and guinea pig ileum. Exchanging various amino acids, e.g. Met by either Pro or Nle, and modifying Phe by adding various substituents in different positions led to compounds which were more effective as insulin secretagogues than CCK<sub>4</sub> itself and even show insulinotropic effects comparable with those of CCK<sub>8</sub> (e.g. compounds M1 and M2 being substituted at Phe). Some compounds which possess electron withdrawing groups on the C-terminal Phe and possess a Pro instead of a Met were especially effective. The CCK<sub>A</sub> receptor antagonist L-364,718, but not by the CCK<sub>B</sub> receptor antagonist L-365,260, inhibited the insulinotropic effects. The synthetic CCK<sub>4</sub> compounds were not selective for the endocrine pancreas: e.g. M1 and M2 had binding activity with respect to rat brain homogenates but no activity with respect to contraction of the guinea pig ileum. The data indicate that some of the newly synthesized CCK tetrapeptides exhibit a high affinity for the CCK receptor of β-cells and have an insulinotropic effect much higher than CCK<sub>4</sub>.

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          Most cited references 4

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          Two brain cholecystokinin receptors: implications for behavioral actions.

          The distribution and relative specificity of cholecystokinin (CCK) receptors in the rat brain was mapped by in vitro autoradiography with [125I]CCK-33. We identified two distinct binding patterns, suggesting two CCK receptor types. The first is widespread and relatively non-specific. The second, localized to a few subcortical nuclei, has the specificity demonstrated for pancreatic CCK receptors. Localization of this receptor type to the area postrema provides a possible entry site into brain for circulating CCK that would distinguish between CCK and gastrin and could mediate some of CCK's behavioral effects.
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            Interaction of CCK with pancreatic acinar cells.

            Recent studies demonstrate that cholecystokinin-like peptides are widely distributed in the CNS as well as in the peripheral nervous system and gastrointestinal tract. Studies with agonists have demonstrated multiple classes of receptors and recently potent receptor antagonists have been described which will distinguish these classes and should allow a better understanding of the role of CCK in various physiological processes. One of the known peripheral physiological functions of CCK is the stimulation of digestive enzymes from pancreatic acinar cells. In recent years the interaction of CCK with pancreatic acinar cells has been extensively studied and significant advances have been made in understanding its cellular basis of action. Robert Jensen and colleagues report on each of these areas.
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              • Article: not found

              Evidence for cholecystokinin receptor subtype in endocrine pancreas

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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2000
                2000
                12 October 2000
                : 53
                : 4
                : 177-184
                Affiliations
                Department of Pharmacology, Institute of Pharmaceutical Sciences, University of Münster, Germany
                Article
                23564 Horm Res 2000;53:177–184
                10.1159/000023564
                11044801
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 6, Tables: 1, References: 42, Pages: 8
                Categories
                Original Paper

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