Relative Potencies of Antagonists of the Luteinizing Hormone Releasing Hormone with Lys8 and Arg8 and Substitutions in Positions 3 ,5 ,6 ,7 and 8

Abstract

Abstract Antagonists of the luteinizing hormone releasing hormone (LHRH) of increased potency is a goal for control of ovulation. In the design and synthesis of 26 decapeptides, emphasis was given to analogs with Lys8 and Arg8 and with various substitutions in positions 3, 5, 6, 7 and 8. Two antagonists, [N-Ac-ᴅ-2-Nal1,ᴅ-pClPhe2,ᴅ-3-Pal3,Ser4,Tyr5,ᴅ-Arg6,Leu7,Lys8,Pro9,ᴅ-Ala10] - NH2 and [N-Ac-ᴅ-2-Nal1.ᴅ-pClPhe2,ᴅ-3-Pal3,Ser4,Arg5,ᴅ-3-Pal6,Leu7,Arg8,Pro9,ᴅ-Ala10]-NH2 showed 80-85% antiovulatory activity (AOA) at 0.25 μg in the rat. The latter antagonist showed 60% AOA at 0.125 μg. Of four pairs of analogs with Arg8 and Lys8, respectively, two pairs favored Lys8 over Arg8 for potency. One pair showed negligible difference and another pair favored Arg8 over Lys8. There is specificity of substitution for potency. In other antagonists, ᴅ-3- Pal3, Tyr5 or Phe5, ᴅ-Arg6 and Leu7 or Nle7 or Val7 and Arg8 were variously effective substitutions for increase of potency and reduction of histamine release.