Antide and related antagonists of luteinizing hormone release with long action and oral activity.

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Abstract
Antide is the decapeptide N-Ac-D-Nal(2),D-Phe-(pCl),D-Pal(3),Ser,LYs(Nic),D-Lys(Nic),Leu,Lys(iPr),Pro,D-Ala-NH2[Nal(2)represents 3-(2-naphthyl)alanine; Phe(p-Cl)represents 3-(4-chlorophenyl)alanine; Pal(3) represents 3-(3-pyridyl)alanine; Lys(Nic) represents N.epsilon.-nicotinollysine; Lys-(iPr) represents N.epsilon.-isopropyllysin], which is an antagonist of luteinizing hormone-releasing hormone (LHRH), which has high antiovulatory activity, releases negligible histamine, and is scheduled for scale-up, safety testing, and evaluation in the experimental primate and in clinical medicine. Thirty-five more peptides were synthesized, designed on antide with variations in positions 5-8. Of these, N-Ac-D-Nal(2),D-Phe(pCl),D-Pal(3), Ser,Lys(Pic) cis-D-Ala(PzAC), Leu,Lys(iPr), Pro, D-Ala-NH2 [Lys(Pic) represents N.epsilon.-picoloyllysine; Ala(PzAC) represents 3-(4-pyrazinylcarbonylaminocyclohexyl)alanine] was not only the most potent but also had higher antiovulatory activity than antide-i.e., 73% per 0.25 .mu.g and 100% per 0.5 .mu.g vs. 36% per 0.5 .mu.g and 100% per 1.0 .mu.g. Antide showed significant (P < 0.001) duration of action when injected at a dose of 10 .mu.g 44 hr before injection of 50 ng of the agonist [D-Qal(3)6]LHR [Qal(3) represents 3-(3-quinoly)alanine]. Antide showed oral antiovulatory activity at 600 .MU.g (73%) and at 1200 .mu.g (100%) with negligible difference between water and corn oil oral formulations.

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