The structural features of effective antagonists of the luteinizing hormone releasing hormone

Abstract

The structure-activity data of 6 years on 395 analogs of the luteinizing hormone releasing hormone (LHRH) have been studied to determine effective substituents for the ten positions for maximal antiovulatory activity and minimal histamine release. The numbers of substituents studied in the ten positions are as follows: (41)(1)-(12)(2)-(12)(3)-(5)(4)-(47)(5)-(52)(6)-(16)(7)-(18)(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 residues in position 5 with cPzACAla being the better substituent. Position 6 was the most flexible and many substituents were effective; particularly 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 histamine release. Pro(9) of LHRH was retained. DAlaNH2 (10) was in the best antagonists.

N5-Pyrazinylcarbonylornithine, an Effective Substituent for Position 5 of Antagonists of LHRH

“…Unauthenticated Download Date | 6/7/19 5:06 AM cPzACAla, Boc-PzLys, and Boc-PzOrn were pre pared in our laboratory [13,14].…”

“…In both antagonists position 5 is occupied by an unnatural amino acid, cis-3-(4-pyrazinylcarbonylaminocyclohexyl)alanine (cPzACAla) (1), which was developed in our lab oratory and successful used in the num ber of LH R H antagonists [9][10][11]. 1 can be synthesized by platinum [12] or rhodium [13] catalyzed hydro genation of Boc-/?-aminophenylalanine, followed * Reprint requests to Prof. Dr. K. Folkers.…”

Real-time analysis of the activities of GnRH and GnRH analogs in ?T3-1 cells by the Cytosensor microphysiometer

“…The structures of the GnRH analogs used were shown in Table I, and their respective maximal responses and EC 50 values were summarized in Table II. The amino acid substitutions and structural modi®cations of the GnRH agonists are mostly at position 6 and the C-terminus, whereas the GnRH antagonists usually have substitutions at the N-terminus [Janecka et al, 1994]. The roles of individual amino acids in GnRH for receptor binding and activation have been extensively evaluated.…”