The kisspeptin (Kp, Kp-54, metastin)/KISS1R system plays crucial roles in regulating the secretion of gonadotropin-releasing hormone. Continuous administration of nonapeptide Kp analogs caused plasma testosterone depletion, whereas bolus administration caused strong plasma testosterone elevation in male rats. To develop a new class of small peptide drugs, we focused on stepwise N-terminal truncation of Kp analogs and discovered potent pentapeptide analogs. Benzoyl-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (16) exhibited high agonist activity for KISS1R and excellent metabolic stability in rat serum. A single injection of a 4-pyridyl analog (19) at the N-terminus of 16 into male Sprague Dawley rats caused a robust increase in plasma luteinizing hormone levels, but unlike continuous administration of nonapeptide Kp analogs, continuous administration of 19 maintained moderate testosterone levels in rats. These results indicated that small peptide drugs can be successfully developed for treating sex hormone deficiency.

中文翻译：

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下丘脑-垂体-性腺轴激活的一类新的五肽KISS1受体激动剂。

Kisspeptin（Kp，Kp-54，metastin）/ KISS1R系统在调节促性腺激素释放激素的分泌中起关键作用。连续施用九肽Kp类似物会导致血浆睾丸激素耗竭，而推注给药会导致雄性大鼠血浆睾丸激素强烈升高。为了开发一类新的小肽药物，我们专注于Kp类似物的N端逐步截短并发现了有效的五肽类似物。苯甲酰-Phe-azaGly-Leu-Arg（Me）-Trp-NH2（16）对KISS1R表现出高激动剂活性，并且在大鼠血清中具有出色的代谢稳定性。在雄性Sprague Dawley大鼠的N端16处单次注射4-吡啶基类似物（19）会导致血浆黄体生成激素水平大幅增加，但与连续施用九肽Kp类似物不同，连续施用19种维持大鼠中度睾丸激素水平的药物。这些结果表明，小肽药物可以成功开发用于治疗性激素缺乏症。