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      A Novel Non-Peptidyl Growth Hormone Secretagogue

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          Abstract

          Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC<sub>50</sub> value of 60 n M. Under the same conditions, His- D-Trp-Ala-Trp- D-Phe-Lys-NH<sub>2</sub> (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC<sub>50</sub> values of 10<sup>-8</sup> and 5 × 10<sup>-10</sup> M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 μ M. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin. These results demonstrate that L-692,429 is the first non-peptidyl secretagogue which has a direct and specific effect on GH release from rat pituitary cells, and its action appears to be mediated through the same receptor and signalling pathway as GHRP-6.

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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
          978-3-8055-5924-9
          978-3-318-01776-2
          1663-2818
          1663-2826
          1993
          1993
          05 December 2008
          : 40
          : 1-3
          : 109-115
          Affiliations
          Department of Growth Biochemistry and Physiology, Merck Research Laboratories, Rahway, N. J. USA
          Article
          183777 Horm Res 1993;40:109–115
          10.1159/000183777
          7905455
          © 1993 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
          Pages: 7
          Categories
          Session IV: Recent Advances in GH Research

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