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 Lys 8 and Arg 8 and with various substitutions in positions 3, 5, 6, 7 and 8. Two antagonists, [N-Ac-ᴅ-2-Nal 1 ,ᴅ-pClPhe 2 ,ᴅ-3-Pal 3 ,Ser 4 ,Tyr 5 ,ᴅ-Arg 6 ,Leu 7 ,Lys 8 ,Pro 9 ,ᴅ-Ala 10 ] - NH 2 and [N-Ac-ᴅ-2-Nal 1 .ᴅ-pClPhe 2 ,ᴅ-3-Pal 3 ,Ser 4 ,Arg 5 ,ᴅ-3-Pal 6 ,Leu 7, Arg 8 ,Pro 9 ,ᴅ-Ala 10 ]-NH 2 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 Arg 8 and Lys 8 , respectively, two pairs favored Lys 8 over Arg 8 for potency. One pair showed negligible difference and another pair favored Arg 8 over Lys 8 . There is specificity of substitution for potency. In other antagonists, ᴅ-3- Pal 3 , Tyr 5 or Phe 5 , ᴅ-Arg 6 and Leu 7 or Nle 7 or Val 7 and Arg 8 were variously effective substitutions for increase of potency and reduction of histamine release.