Skip Navigation

This Article
Right arrow FREE Full Text (PDF ) Freely available
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Rivier, J.
Right arrow Articles by Rivier, C.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Rivier, J.
Right arrow Articles by Rivier, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Reproduction, Vol. 11, No. suppl_3, pp. 133-147, 1996
© 1996 European Society of Human Reproduction and Embryology

Dose relationship between GnRH antagonists and pituitary suppression

J. Rivier1,5, G.-C Jiang1, S.L. Lahrichi1, J. Porter1, S.C. Koerber1, J. Rizo2, A. Corrigan1, L. Gierasch3, A. Hagler4, W. Vale1 and C. Rivier1

1 The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute La Jolla, CA 92037 2 Department of Pharmacology, University of Texas, Southwestern Medical Center Dallas, TX 75235 3 University of Massachusetts, Department of Chemistry Amherst, MA 01003 4 Biosym Technologies Inc., San Diego, CA 92121, USA

Correspondence: 5To whom correspondence should be addressed

While the clinical significance of gonadotrophin-releasing hormone (GnRH) agonists is well recognized, the potential use of GnRH antagonists in humans awaits the availability of potent analogues with no untoward side-effects. We have designed, synthesized and tested several hundred linear and cyclic analogues (agonists and antagonists) of GnRH in different rat models; some have high histamine releasing activity and others have poor solubility in aqueous buffers with a pH >6.0. Furthermore, we have identified analogues exhibiting short (<12 h), intermediate (12–72 h) and long (>72 h) duration of action in the rat (50 µg s.c. dose/rat). We have concluded that the basis for such resistance to degradation and elimination must be specific. In order to gain further information on the optimal nature and sterical requirements of side-chains, preliminary experiments were carried out using betidamino acids. Finally, mono- and dicyclic analogues of GnRH with potencies comparable with that of the most potent linear analogues were also obtained. Our approach to the development of such analogues included the use of nuclear magnetic resonance and computational techniques as well as that of state-of-the-art synthetic approaches. We intend to use the information derived from these structure/activity relationship studies to design conformationally-similar peptido-mimetics.

Key words: acyline/azaline B/betidamino acids/drug design/GnRH antagonists


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.