Synthesis and biological activity of some very hydrophobic superagonist analogues of luteinizing hormone-releasing hormone.
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).
D000596:Amino Acids / Q000032:analysis; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D003278:Contraceptives, Oral, Hormonal; D004971:Estrus / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility
D000596:Amino Acids; D003278:Contraceptives, Oral, Hormonal; D010455:Peptides; D007987:Gonadotropin-Releasing Hormone