Growth Hormone Secretagogues PDF
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Serono Symposia USA Norwell, Massachusetts Springer New York Berlin Heidelberg Barcelona Budapest Hong Kong London Milan Paris Santa Clara Singapore Tokyo PROCEEDINGS IN THE SERONO SYMPOSIA USA SERIES GROWTH HORMONE SECRETAGOGUES Edited by Barry B. Bercu and Richard F. Walker CELLULAR AND MOLECULAR REGULATION OF TESTICULAR CELLS Edited by Claude Desjardins GENETIC MODELS OF IMMUNE AND INFLAMMATORY DISEASES Edited by Abul K. Abbas and Richard A. Flavell MOLECULAR AND CELLULAR ASPECTS OF PERIIMPLANTATION PROCESSES Edited by S.K. Dey THE SOMATOTROPHIC AXIS AND THE REPRODUCTIVE PROCESS IN HEALTH AND DISEASE Edited by Eli Y. Adashi and Michael O. Thorner GHRH, GH, AND IGF-I: Basic and Clinical Advances Edited by Marc R. Blackman, S. Mitchell Harman, Jesse Roth, and Jay R. Shapiro IMMUNOBIOLOGY OF REPRODUCTION Edited by Joan S. Hunt FUNCTION OF SOMATIC CELLS IN THE TESTIS Edited by Andrzej Bartke GLYCOPROTEIN HORMONES: Structure, Function, and Clinical Implications Edited by Joyce W. Lustbader, David Puett, and Raymond W. Ruddon GROWTH HORMONE II: Basic and Clinical Aspects Edited by Barry B. Bercu and Richard F. Walker TROPHOBLAST CELLS: Pathways for Maternal-Embryonic Communication Edited by Michael J. Soares, Stuart Handwerger, and Frank Talamantes IN VITRO FERTILIZATION AND EMBRYO TRANSFER IN PRIMATES Edited by Don P. Wolf, Richard L. Stouffer, and Robert M. Brenner OVARIAN CELL INTERACTIONS: Genes to Physiology Edited by Aaron J.W. Hsueh and David W. Schomberg CELL BIOLOGY AND BIOTECHNOLOGY: Novel Approaches to Increased Cellular Productivity Edited by Melvin S. Oka and Randall G. Rupp PREIMPLANTATION EMBRYO DEVELOPMENT Edited by Barry D. Bavister MOLECULAR BASIS OF REPRODUCTIVE ENDOCRINOLOGY Edited by Peter C.K. Leung, Aaron l.W. Hsueh, and Henry G. Friesen MODES OF ACTION OF GnRH AND GnRH ANALOGS Edited by William F. Crowley, Jr., and P. Michael Conn Continued after Index Serono Symposia USA Norwell, Massachusetts Barry B. Bercll Richard F. Walker Editors Growth Hormone Secretagogues With 138 Figures , Springer Barry B. Bercu, M.D. Richard F. Walker, Ph.D. Pediatric Endocrinology All Children's Hospital St. Petersburg, FL 33701 USA Proceedings of the International Symposium on Growth Hormone Secretagogues sponsored by Serono Symposia USA, Inc., held December 8 to 11, 1994, in St. Petersburg Beach, Florida. For information on previous volumes, please contact Serono Symposia USA, Inc. Library of Congress Cataloging·in·Publication Data Growth hormone secretagogues/edited by Barry B. Bercu and Richard F. Walker. p. cm.-(Proceedings of the Serono Symposia USA series;) "Proceedings of the International Symposium on Growth Hormone Secretagogues sponsored by Serono Symposia USA, Inc., held December 8 to 11, 1994, in St. Petersburg Beach, Florida"-T.p. verso. Includes bibliographical references and index. ISBN-13:978-1-4612-7526-8 e-ISBN-13: 978-1-4612-2396-2 DOl: 10.1007/978-1-4612-2396-2 1. Growth hormone releasing factor-Congresses. 2. Somatotropin Congresses. L Bercu, Barry B. II. Walker, Richard F., 1939- . III. International Symposium on Growth Hormone Secretagogues (1994: Saint Petersburg Beach, Fla.) IV. Series: Proceedings of the Serono Symposia. QP572.G75G76 1996 612.6-dc20 96-632 Printed on acid-free paper. © 1996 Springer-Verlag New York, Inc. Softcover reprint of the hardcover 1s t edition 1996 All rights res'erved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New York, NY 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use of general descriptive names, trade names, trademarks, etc., in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordingly by used freely by anyone. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors, nor the editors, nor the publisher, nor Serono Symposia USA, Inc., nor Serono Laboratories, Inc., can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Springer-Verlag New York, Inc., provided that the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, USA (Telephone: (508) 750-84(0), stating the ISBN number, the volume title, and the first and last page numbers of article copied. The copyright owner's consent does not include copying for general distribution, promotion, new works, or resale. In these cases, specific written permission must first be obtained from the publisher. Production coordinated by Chernow Editorial Services, Inc., and managed by Francine McNeill; manufac turing supervised by Jacqui Ashri. Typeset by Best-set Typesetter Ltd., Hong Kong. 987654321 INTERNATIONAL SYMPOSIUM ON GROWTH HORMONE SECRETAGOGUES Scientific Committee Barry B. Bercu, M.D., Co-Chairman Richard F. Walker, Ph.D., Co-Chairman Michael Berelowitz, M.B., Ch.B. Lawrence A. Frohman, M.D. John L. Gueriguian, M.D. Hiroo Imura, M.D. Zvi Laron, M.D. Roy G. Smith, Ph.D. William B. Wehrenberg, Ph.D. Organizing Secretary Leslie Nies Serono Symposia USA, Inc. 100 Longwater Circle Norwell, Massachusetts Preface The traditional concept of a neuroendocrine mechanism for regulation of growth hormone (GH) secretion is based in large part on the work of Roger Guillemin. The work of Dr. Guillemin, who was awarded the 1977 Nobel Prize in Physiology and Medicine, supported the view that quantita tive change in GH secretion was the net result of pituitary stimulation and inhibition by the hypothalamic neurohormones, GH releasing hormone (GHRH), and somatostatin (somatotropin release inhibiting factor; SRIF), respectively. During the 1970s, another endocrine research pioneer, Dr. Cyril Bowers, discovered that structural modification of enkephalin re sulted in a family of peptides with GH releasing properties. These com pounds, simply called GH releasing peptide (GHRP), were originally thought to mimic GHRH. However, upon subsequent investigation they were found to supplement the activity of the natural hormone through a different mechanism. Nearly two decades after their discovery, the differ ences between GHRP and GHRH have been described by many different laboratories throughout the world. The complementary GH secretagogues have different binding sites, second messengers, and effects on gene expres sion. Based on these differences, it has been suggested that expansion of the original two hormone mechanisms for GH regulation to include a third molecule may be appropriate, even though the naturally occurring ana logue of GHRP has not yet been identified. Despite our lack of knowledge concerning the natural product mimicked by GHRP, clinical development of the new family of GH secretagogues for diagnostic and therapeutic purposes has begun in earnest. The practical application of the GHRPs in medicine may be likened to the use of mor phine for its therapeutic benefits, years before the endorphins were discov ered. The rapid growth of research and development of GHRPs as drug products can be most likely attributed to the discovery that the prototype, GHRP-6 (growth hormone releasing hexapeptide; His-DTrp-Ala-Trp DPhe-Lys-NHz) was orally active, although its bioavailability was relatively low. Nonetheless, recognition of its oral activity led to the discovery of truncated peptides and nonpeptidyl mimics with significantly greater vii viii Preface bioavailability. These compounds are now being actively developed for various and sundry purposes including such different maladies as growth retardation and osteoporosis. The broad range of potential applications for increased growth hormone secretion for treating disease in pediatric and geriatric populations makes GH secretagogues increasingly important pharmacotherapeutic entities. Recognizing the significant advances in GH secretagogue research that have occurred over the past two decades, we felt that it was appropriate to organize a meeting specifically devoted to discussion of the GHRH and GHRP families of molecules. Because of their significant research contribu tions, Drs. Guillemin and Bowers began the meeting with historical per spectives on their independent discoveries of the different GH secretagogues. After an interesting and reflective session on the origins of GH secretagogue research, the meeting progressed to discussions of con temporary methods for chemical modification of GH secretagogues. The presentations focused on specific substitutions on the GHRH molecule that enhance its potency. In addition, theoretical models for designing xenobiotic GHRPs, and methods for practical application of these prin ciples to create more active, truncated varieties of the prototypical mol ecules as well as to produce new, nonpeptidyl mimics of GHRP were presented. The structure, function, and regulation of the receptor for GHRH was also discussed to better understand how secretagogues elicit their specific activity at the level of the pituitary gland. Consistent with this topic, subsequent discussions dealt with cellular and molecular properties of the different GH secretagogues, focusing on topics ranging from second messenger utilization to gene expression. As a logical extension, the meet ing progressed to evaluation of physiologic actions of GHRH and GHRP at the systems and organism level. These sessions included talks on basic and clinical aspects of GH secretagogue research dealing with such subjects as animal models for evaluating GH secretagogue potency and efficacy, pitu itary mammosomatotroph transdifferentiation as influenced by GH secre tagogues, behavioral effects of exposure to these compounds, and clinical utility of secretagogue administration in treating GH-deficient and obese children. The final session touched upon possible alternative uses for GH secretagogues, which included immunotherapy as well as treatment of osteoporosis and other degenerative and pathologic concomitants of aging. This book, which presents specific important details of each author's oral presentation, provides the reader an opportunity to view the birth of GH secretagogue research from the eyes of the world-renowned scientists who pioneered the field to those of contemporary investigators using state-of the-art techniques to bring theoretical concepts to clinical utility. Accord ingly, we wish to thank the scientific committee, session chairs, speakers, and poster presenters for their outstanding contributions to the symposium and to the publication of this book. We are especially grateful to Leslie Nies Preface ix and her superb staff at Serono Symposia USA, Inc., for their unflagging assistance with organization of the meeting, considerable financial assis tance, and their patience throughout the process of organizing the sympo sium and publishing this volume. BARRY B. BERCU RICHARD F. WALKER Contents Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VB Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Part I. Overview: Historical Perspective 1. Growth Hormone Releasing Factor: A Brief History of Its Time... .. . . . . . . . ... . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . 3 ROGER GUILLEMIN 2. Xenobiotic Growth Hormone Secretagogues: Growth Hormone Releasing Pep tides . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 CYRIL Y. BOWERS Part II. Chemistry of Growth Hormone Secretagogues 3. Synthetic Analogues of Growth Hormone Releasing Factor (GHRF) with Improved Pharmaceutical Properties 31 TERESA M. KUBIAK, ALAN R. FRIEDMAN, AND W. MICHAEL MOSELEY 4. Structure, Function, and Regulation of the Pituitary Receptor for Growth Hormone Releasing Hormone. . . . . . . 53 KELLY E. MAYO, PAUL A. GODFREY, VENITA DEALMEIDA, AND TERESA L. MILLER 5. Computer-Assisted Modeling of Xenobiotic Growth Hormone Secretagogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 FRANK A. MOMANY AND CYRIL Y. BOWERS xi Contents XlI 6. Growth Hormone Releasing Peptides 85 ROMANO DEGHENGHI 7. Nonpeptidyl Growth Hormone Secretagogues . . . . . . . . . . . . . 103 MATTHEW J. WYVRATT 8. A Weak Substance P Antagonist Inhibits L-692,585-Stimulated GH Release in Swine. . . . . . . . . . . . . . . 119 C. CHANG, E. RICKES, L. McGUIRE, S. COSGROVE, E. FRAZIER, H. CHEN, K. CHENG, R. SMITH, AND G. HICKEY 9. Growth Hormone Releasing Hormone Receptor in Human Breast Cancer Cell Line MCF-7 ......................... 127 GREGOIRE PREVOST, NATHALIE VEBER, LUCIEN ISRAEL, AND PHILIPPE PLANCHON Part III. Cellular and Molecular Properties of Growth Hormone Secretagogues 10. Cellular Physiology of Growth Hormone Releasing Hormone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 LAWRENCE A. FROHMAN 11. Mechanism of Action of GHRP-6 and Nonpeptidyl Growth Hormone Secretagogues . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 147 Roy G. SMITH, KANG CHENG, SHENG-SHUNG PONG, REID LEONARD, CHARLES J. COHEN, JOSEPH P. ARENA, GERARD J. HICKEY, CHING H. CHANG, TOM JACKS, JENNIFER DRISKO, lAIN C.A.F. ROBINSON, SUZANNE L. DICKSON, AND GARETH LENG 12. Metabolic Regulation of Growth Hormone Secretagogue Gene Expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 MICHAEL BERELOWITZ AND JOHN F. BRUNO Part IV. Physiology of Growth Hormone Secretagogues 13. The Role of Growth Hormone Releasing Hormone (GHRH) and Growth Hormone (GH) in the Onset of Puberty and During Glucocorticoid-Altered Growth. . . . . . . . . . . . . . . . . . . 185 LISA K. CONLEY, MICHEL L. AUBERT, ANDREA GruSTINA, AND WILLIAM B. WEHRENBERG
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