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动物实验研究表明AF-2364是一种很有潜力的男性避孕药候选化合物.这一化合物通过干扰精子细胞与支持细胞间的黏附功能,可逆地诱导精母细胞以及精细胞从生精上皮丢失,但不影响精原细胞,从而导致给药大鼠不育.一旦药物代谢完成,精原细胞可重新开始精子发生,动物即可恢复生育能力.AF-2364能引起细胞骨架肌动蛋白的聚集和解聚,导致支持细胞与精子细胞间黏附功能降低,最后使未成熟精母细胞和精子细胞从生精上皮丢失.其机制可能是先激活整联蛋白/层粘连蛋白复合体及睾丸素,然后激活下游RhoB/ROCK/LIM激酶/肌动蛋白素或FAK/PI3激酶/p130Cas/MAP激酶通路.此外,AF-2364是一种较强的囊性纤维跨膜传导调节因子(CFTR)抑制剂,具有显著的抗生育作用,其作用可能是通过干扰CFTR通道活性,影响生殖道的体液微环境,从而影响精母细胞发育,精子细胞在附睾内成熟以及精子获能和顶体反应.探索AF-2364在男性生殖系统中作用的分子机制,对开发新一代男性避孕药具有重要意义.
Animal studies have shown that AF-2364 is a potential male contraceptive candidate compound that reversibly induces the loss of spermatocytes and sperm cells from the seminiferous epithelium by interfering with the adhesion between sperm cells and supporting cells, But does not affect the spermatogonia, leading to sterility in the administration rat.Once the drug metabolism is completed, spermatogonia can resume spermatogenesis and the animals can restore fertility.AF-2364 can cause cytoskeletal actin aggregation and solution Poly, leading to support cells and sperm cell adhesion decreased, and finally so that immature spermatocytes and sperm cells lost from the seminiferous epithelium.The mechanism may be activated first integrin / laminin complex and testosterone, and then activated Downstream RhoB / ROCK / LIM kinase / actin or FAK / PI3 kinase / p130Cas / MAP kinase pathway.Furthermore, AF-2364 is a potent cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor with Significant anti-fertility effect, its role may be by interfering with CFTR channel activity, affecting the reproductive tract of the humoral microenvironment, thus affecting the development of spermatocytes, sperm cells mature in the epididymis and sperm were And acrosome reaction. Explore the molecular mechanisms of AF-2364 role in the male reproductive system, it is important for the development of a new generation of male contraceptives.