低组胺释放副作用的GnRH拮抗剂的设计合成及活性评价

根据肽类组胺释放剂具有多个碱性氨基酸的结构特点, 将具有羧基结构的基团引入促性腺激素释放激素(GnRH)的不同位置, 合成了一系列新的GnRH类似物, 并进行了大鼠体内抑制睾酮释放的生物活性评价及大鼠腹腔肥大细胞中的促组胺释放副作用评价. 结果表明, 某些带有酸性基团的GnRH类似物不仅组胺释放副作用大大降低, 而且保留了原有的生物活性. 该结果为研发具有低组胺释放副作用的安全型GnRH拮抗剂药物提供了新的构效关系信息.

Design, Synthesis and Bioactivity Evaluation of GnRH Antagonists with Low Histamine-releasing Potency

The histamine-releasing potency of gonadotropin-releasing hormone(GnRH) antagonists induced the serious side effect in clinical application. Because the histamine-releasing peptides usually had one or more basic amino acids. Therefore, the carboxyl groups were introduced to the position 6, 8 or N-terminal of GnRH in order to develop the safe GnRH antagonists, and novel GnRH analogues were synthesized. The experimental results showed that some GnRH analogues with carboxyl group not only have low histamine-releasing potency, but also retained intrinsical testesterone-inhibiting bioactivity. It suggested the method of decreasing the histamine-releasing potency of the peptides by introducing the carboxyl groups was feasible.