Potent pituitary-gonadal axis suppression and extremely low anaphylactoid activity of a new gonadotropin releasing hormone (GnRH) receptor antagonist 'azaline B'
| Autor: | Muh-Tsann Lai, Tom Kirchner, Carolyn A. Campen, Pat Kraft, Audrey Phillips, Jean Rivier, Do Won Hahn |
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| Rok vydání: | 1995 |
| Předmět: |
Agonist
Ovulation endocrine system medicine.medical_specialty medicine.drug_class Ovariectomy Guinea Pigs Molecular Sequence Data Gonadotropin-releasing hormone Biology Biochemistry Gonadotropin-Releasing Hormone Follicle-stimulating hormone Internal medicine medicine Animals Amino Acid Sequence Rats Wistar Anaphylaxis Pharmacology Histrelin Pituitary gonadal axis Luteinizing Hormone Receptor antagonist Rats Endocrinology Pituitary Gland Female Gonadotropin Follicle Stimulating Hormone Luteinizing hormone Oligopeptides hormones hormone substitutes and hormone antagonists Receptors LHRH medicine.drug |
| Zdroj: | Biochemical pharmacology. 49(9) |
| ISSN: | 0006-2952 |
| Popis: | We report here the biological characterization of azaline B, a new gonadotropin releasing hormone (GnRH) receptor antagonist, with the following amino acid sequence: [Ac- d -Nal1, d -Cpa2, d -Pal3, Aph5(atz), d -Aph6(atz), Ilys8, d -Ala10]-GnRH. Azaline B was shown to suppress several reproductive processes in rats including ovulation, and had very low anaphylactoid activity compared with other GnRH antagonists. Azaline B inhibited histrelin (a GnRH agonist)-mediated follicle stimulating hormone (FSH) and luteinizing hormone (LH) release from cultured rat pituitary cells. Three antagonists ([Nal-Glu]-GnRH, [Nal-Lys]-GnRH (“antide”), and azaline B) inhibited 0.1 nM histrelin-mediated gonadotropin release to baseline levels with ec 50 values of approximately 0.6 nM. Azaline B, when injected s.c. into rats on the afternoon of proestrus, was more potent at inhibiting ovulation than either [Nal-Glu]-GnRH or [Nal-Lys]-GnRH. The relative order of antiovulatory potencies of the three antagonists was azaline B > [Nal-Glu]-GnRH > [Nal-Lys]-GnRH. Similar azaline B potency was shown by its ability to suppress gonadotropin levels in castrated rats. The improved selectivity of azaline B was demonstrated when it was compared with other GnRH antagonists in the cutaneous anaphylactoid assay (local wheal response) in rats. Results with azaline B were not significantly different from results with vehicle in this assay. [Nal-Glu]-GnRH was more than twice as potent as [Nal-Lys]-GnRH in stimulating a wheal response. Furthermore, the maximal wheal response produced by azaline B was only 0.6 times that of [Nal-Lys]-GnRH, currently one of the most selective antagonists identified. Finally, both azaline B and [Nal-Lys]-GnRH were much less potent than [Nal-Glu]-GnRH in the guinea pig cardiopulmonary anaphylactoid assay after i.v. administration. These data show that azaline B is a potent and selective GnRH receptor antagonist with little or no anaphylactoid activity in animal models, and therefore has potential for use in the treatment of many reproductive endocrine disorders, as well as for use as a contraceptive. |
| Databáze: | OpenAIRE |
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