Dose relationship between GnRH antagonists and pituitary suppression
| Autor: | Arnold T. Hagler, John S. Porter, Anne Z. Corrigan, Jean Rivier, Guangcheng Jiang, S L Lahrichi, Lila M. Gierasch, Steven C. Koerber, Catherine Rivier, Josep Rizo, Wylie Vale |
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| Rok vydání: | 1996 |
| Předmět: |
Ovulation
Agonist Pituitary gland medicine.medical_specialty medicine.drug_class Gonadotropin-releasing hormone Biology Pharmacology Gonadotropin-releasing hormone antagonist Gonadotropin-Releasing Hormone chemistry.chemical_compound Hormone Antagonists Internal medicine medicine Animals Structure–activity relationship Amino Acid Sequence Dose-Response Relationship Drug Rehabilitation Obstetrics and Gynecology Rats medicine.anatomical_structure Endocrinology Reproductive Medicine chemistry Pituitary Gland Female Gonadotropin Histamine Hormone |
| Zdroj: | Human Reproduction. 11:133-147 |
| ISSN: | 1460-2350 0268-1161 |
| DOI: | 10.1093/humrep/11.suppl_3.133 |
| Popis: | To whom correspondence should be addressedWhile the clinical significance of gonadotrophin-releasing hormone (GnRH)agonists is well recognized, the potential use of GnRH antagonists in humansawaits the availability of potent analogues with no untoward side-effects. Wehave designed, synthesized and tested several hundred linear and cyclic analogues(agonists and antagonists) of GnRH in different rat models; some have highhistamine releasing activity and others have poor solubility in aqueous bufferswith a pH >6.0. Furthermore, we have identified analogues exhibiting short( 72 h) duration of action in the rat(50 |Xg s.c. dose/rat). We have concluded that the basis for such resistance todegradation and elimination must be specific. In order to gain further informationon the optimal nature and sterical requirements of side-chains, preliminaryexperiments were carried out using betidamino acids. Finally, mono- and dicyclicanalogues of GnRH with potencies comparable with that of the most potentlinear analogues were also obtained. Our approach to the development of suchanalogues included the use of nuclear magnetic resonance and computationaltechniques as well as that of state-of-the-art synthetic approaches. We intend touse the information derived from these structure/activity relationship studies todesign conformationally-similar peptido-mimetics.Key words: acyline/azaline B/betidamino acids/drug design/GnRH antagonists |
| Databáze: | OpenAIRE |
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