Design, Synthesis, and Biological Evaluation of Novel Investigational Nonapeptide KISS1R Agonists with Testosterone-Suppressive Activity

Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, metastin(45–54), possesses a 10-fold higher receptor-binding affinity than full-length metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [d-Tyr45,d-Trp47,azaGly51,Arg(Me)53]metastin(45–54) with improved serum stability compared with metastin(45–54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45–47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [d-Tyr46,d-Pya(4)47,azaGly51,Arg(Me)53]metastin(46–54), compound 26, which displayed KISS1R binding affinities comparable to metastin(45–54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length metastin analog to possess testosterone suppressive activit...