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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8298-8307
Main Authors: Asami, Taiji, Nishizawa, Naoki, Matsui, Hisanori, Nishibori, Kimiko, Ishibashi, Yoshihiro, Horikoshi, Yasuko, Nakayama, Masaharu, Matsumoto, Shin-ichi, Tarui, Naoki, Yamaguchi, Masashi, Matsumoto, Hirokazu, Ohtaki, Tetsuya, Kitada, Chieko
Format: Article
Language:English
Subjects:
Animals
CHO Cells
Cricetulus
Drug Design
Drugs, Investigational - chemical synthesis
Drugs, Investigational - chemistry
Drugs, Investigational - pharmacology
Humans
Kisspeptins - blood
Kisspeptins - chemical synthesis
Kisspeptins - pharmacology
Male
Mice
Molecular Conformation
Rats
Rats, Wistar
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Receptors, Kisspeptin-1
Structure-Activity Relationship
Testosterone - antagonists & inhibitors
Testosterone - blood
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Summary: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 activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401056w