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Synthesis and biological activity of some very hydrophobic superagonist analogues of luteinizing hormone-releasing hormone.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1982 Jul; Vol. 25 (7), pp. 795-801. - Publication Year :
- 1982
-
Abstract
- The effect of increased hydrophobicity at position 6 of luteinizing hormone-releasing hormone (LH-RH) has been investigated by the incorporation of a series of 15 very hydrophobic, unnatural D-amino acids at this position. The unnatural amino acids studied can be considered analogues of phenylalanine with carbocyclic aromatic side chains consisting of substituted phenyl (e.g., 2,4,6-trimethylphenyl, p-biphenyl) or polycyclic aromatic (e.g., naphthalene, anthracene) units. When enzymatic resolution (subtilisin Carlsberg) of the most hydrophobic amino acids failed, the racemic amino acids were incorporated, and the diastereomeric LH-RH analogues were resolved by preparative high-performance liquid chromatography. The analogues were synthesized by the solid-phase technique. All of the synthetic compounds were very potent LH-RH superagonists, but [6-(3-(2-naphthyl)-D-alanine)]LH-RH, [6-(3-(2-naphthyl)-D-alanine), 7-(N alpha-methylleucine)]LH-RH and [6-(3-(2,4,6-trimethylphenyl)-D-alanine)]LH-RH appear to be among the most potent LH-RH agonist analogues yet reported when tested in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds [ED50 approximately 7 x 10(-8) g; twice daily in saline]. These analogues are twice as potent as [D-Trp6,ProNHEt9]LH-RH in this assay system (i.e., approximately 200 times the potency of LH-RH).
- Subjects :
- Amino Acids analysis
Animals
Chemical Phenomena
Chemistry
Chromatography, High Pressure Liquid
Contraceptives, Oral, Hormonal
Estrus drug effects
Female
Gonadotropin-Releasing Hormone chemical synthesis
Gonadotropin-Releasing Hormone pharmacology
Peptides chemical synthesis
Pregnancy
Rats
Rats, Inbred Strains
Solubility
Gonadotropin-Releasing Hormone analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 25
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 7050383
- Full Text :
- https://doi.org/10.1021/jm00349a006