Influence on binding affinity of leuprolide analogues modified in position 6 with alpha,alpha-dialkyl amino acids

摘要

The pivotal role that LHRH and its analogues play in the modulation of reproductive functions have attracted considerable scientific interest because of their usefulness in the treatment of endocrine-based diseases such as prostate and breast cancer,endometriosis and precocious puberty.LHRH has been the subject of intense structure-activity relationship(SAR)studies aimed at elucidating its mechanism of action and identifying drug candidates(agonists and antagonists),which have been extensively studied in the clinic later on.Agonistic analogues of LHRH,represented by Leuprolide([DLeu~6,desGly~(10)]-LHRH-NHEt),have been widely used in oncology and gynaecology for nearly two decades.In this study,we report the synthesis of new LHRH analogues bearing the Fujino modification and substituted at position 6(Gly~6)by alpha,alpha-dialkyl amino ' acids(Aib,Deg).In addition,the affinities of new analogues for the LHRH receptor were determined by competition binding experiments in mouse anterior pituitary alpha T3-l cells.