872719-17-0Relevant articles and documents
Physicochemically and pharmacokinetically stable nonapeptide kiss1 receptor agonists with highly potent testosterone-suppressive activity
Asami, Taiji,Nishizawa, Naoki,Matsui, Hisanori,Takatsu, Yoshihiro,Suzuki, Atsuko,Kiba, Atsushi,Terada, Michiko,Nishibori, Kimiko,Nakayama, Masaharu,Ban, Junko,Matsumoto, Shin-Ichi,Tarui, Naoki,Ikeda, Yukihiro,Yamaguchi, Masashi,Kusaka, Masami,Ohtaki, Tetsuya,Kitada, Chieko
, p. 6105 - 6115 (2014)
Modifications of metastin(45-54) produced peptide analogues with higher metabolic stability than metastin(45-54). N-terminally truncated nonapeptide 4 ([d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me) 53]metastin(46-54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser 49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp 47,Thr49,azaGly51,Arg(Me)53,Trp 54]metastin(46-54) (14) showed 2-fold greater [Ca2+] i-mobilizing activity than metastin(45-54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr46,d-Trp47,Thr 49,azaGly51,Arg(Me)53,Trp54] metastin(46-54)). With continuous administration, 22 possessed 10-50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic-pituitary-gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases.
