Progress towards the development of non-peptide orally-active gonadotropin-releasing hormone (GnRH) antagonists: therapeutic implications
| Autor: | R S Struthers, Y F Zhu, C Chen, R P Millar |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Agonist
endocrine system medicine.medical_specialty medicine.drug_class medicine.medical_treatment Administration Oral Gonadotropin-releasing hormone Pharmacology Biology Peptide hormone Gonadotropic cell Gonadotropin-Releasing Hormone Structure-Activity Relationship Receptors Gonadotropin Contraceptive Agents Internal medicine medicine Animals Humans Receptor General Medicine Rats Macaca fascicularis Steroid hormone Endocrinology Hypothalamus Models Animal Female hormones hormone substitutes and hormone antagonists Forecasting Protein Binding Hormone |
| Zdroj: | British Medical Bulletin. 56:761-772 |
| ISSN: | 1471-8391 0007-1420 |
| Popis: | Gonadotropin-releasing hormone (GnRH) is a decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly.NH2) which is produced from a precursor polypeptide in hypothalamic neurons and secreted in a pulsatile fashion to stimulate the secretion of LH and FSH via its interaction with a cognate receptor on gonadotropes. Low doses of the native peptide delivered in a pulsatile manner to mimic that found in the hypothalamic portal vessels restore fertility in hypogonadal patients, and are also effective in treating cryptorchidism and delayed puberty. Administration of high doses of GnRH, or agonist analogues, causes desensitization of the gonadotrope with consequent decline in gonadal gametogenesis and steroid and peptide hormone synthesis. This phenomenon finds extensive therapeutic application in clinical medicine in a wide spectrum of disease (Table 1). In addition, GnRH analogues have promise as new generation male and female contraceptives in conjunction with steroid hormone replacement. GnRH antagonists inhibit the reproductive system through competition with endogenous GnRH for the receptor and, in view of their rapid effects, are being increasingly used for the above mentioned applications. The peptide agonists and antagonists currently available require parenteral administration, typically in the form of long-acting depots. A new generation of non-peptide GnRH antagonists are beginning to emerge which should allow oral administration and, therefore, may provide greater flexibility of dosing, lower costs and increased patient acceptance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|