THE STRUCTURAL FEATURES OF EFFECTIVE ANTAGONISTS OF THE LUTEINIZING-HORMONE-RELEASING HORMONE

The structure-activity data of 6 years on 395 analogs of the luteinizi ng hormone releasing hormone (LHRH) have been studied to determine eff ective substituents for the ten positions for maximal antiovulatory ac tivity and minimal histamine release. The numbers of substituents stud ied in the ten positions are as follows: 4)-(47)(5)-(52)(6)-(16)(7)-(1 8)(8)-(4)(9)-(8)(10). In position 1, DNal and DQal were effective with the former being more frequently the better substituent. DpClPhe was uniquely effective in position 2. Positions 3 and 4 are very sensitive to change. D3Pal in position 3 and Ser in position 4 of LHRH were in the best antagonists. PicLys and cPzACAla were the most successful res idues in position 5 with cPzACAla being the better substituent. Positi on 6 was the most flexible and many substituents were effective; parti cularly DPicLys. Leu(7) was most often present in the best antagonists . In position 8, Arg was effective for both antiovulatory activity and histamine release; ILys was effective for potency and lesser histamin e release. Pro(9) of LHRH was retained. DAlaNH(2)(10) was in the best antagonists.