Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity.

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 Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr46,d-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]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,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46–54)). With continuous administration, 22 possessed 10–50...