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Synthesis and biological activities of pseudopeptide analogues of LH-RH: agonists and antagonists
Authors:A F Spatola  N S Agarwal  A L Bettag  J A Yankeelov  C Y Bowers  W W Vale
Institution:1. Department of Chemistry, University of Louisville, Louisville, KY 40292 USA;2. Department of Biochemistry, University of Louisville, Louisville, KY 40292 USA
Abstract:Using solid phase methods, seven agonist and antagonist analogues of LH-RH have been prepared containing enzyme-resistant CH2S linkages as selected amide bond replacements. Agonists modified at the 5–6, 6–7 and 9–10 position had 2, < 0.1, and 10% of the invitro activity of LH-RH, respectively. Among potential antagonists, 6–7 position analogues showed only minimal inhibitory activity but N- and C-terminal modified analogues retained substantial LH-RH-LH and FSH inhibitory activity. In addition, a 1–2 position methylene thioether analogue of the parent Ac-Pro1, D-Phe2, D-Trp3,6]LH-RH antagonist was completely inhibitory at 30 ng invitro and represents the first such structure-modification that may be at least as active as its corresponding amide linked congener. However, neither 1–2 nor 9–10 methylene thioether position antagonists showed invivo antiovulatory activity at the 250 μg level.
Keywords:To whom correspondence should be addressed  
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