Inhibition of Follicle-Stimulating Hormone-Induced Preovulatory Follicles in Rats Treated with a Nonsteroidal Negative Allosteric Modulator of Follicle-Stimulating Hormone Receptor
Inhibition of Follicle-Stimulating Hormone-Induced Preovulatory Follicles in Rats Treated with a Nonsteroidal Negative Allosteric Modulator of Follicle-Stimulating Hormone Receptor
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DOI：
10.1095/biolreprod.113.109397
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发表时间：
2014-01-01
影响因子：
3.6
通讯作者：
Poli, Sonia M.
中科院分区：
文献类型：
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作者：
Dias, James A.;Campo, Brice;Poli, Sonia M.
我们先前描述了FSHR的负变构调节剂（NAM）（ADX 61623），其阻断FSH诱导的cAMP和孕酮产生，但不阻断雌二醇产生。FSHR NAM不影响FSH诱导的排卵前卵泡发育，这一点通过对hCG排卵后壶腹中FSH依赖的卵母细胞数量缺乏影响而得到证明。一个目标是开发一种非甾体避孕药。为此，使用人FSHR进行的高通量筛选鉴定了另外一种非甾体小分子（ADX 68692）。尽管ADX 68692在抑制cAMP和孕酮产生方面的表现与ADX 61623相似，但在体外大鼠颗粒原代细胞培养生物测定中，它也抑制FSH诱导的雌二醇。当在外源性FSH给药前皮下注射或经口给药未成熟的非周期性雌性大鼠时，发现ADX 68692减少了从壶腹中回收的卵母细胞数量。通过经口灌胃给予25 mg/kg和10 mg/kg ADX 68692，破坏了成熟雌性大鼠的发情周期。在最高试验剂量（25 mg/kg）下，55%与成熟雄性同居的动物具有着床部位，而10 mg/kg组为33%，对照组为77%。令人惊讶的发现是，结构类似物ADX 68693虽然以与ADX 68692类似的功效有效地阻断孕酮产生，但不阻断雌激素产生，并且尽管口服利用度更好，但即使以100 mg/kg使用时也不减少壶腹中发现的卵母细胞的数量。这些数据表明，由于FSHR的偏向性拮抗作用，非甾体避孕要求必须有效阻断FSHR类固醇生成途径的两臂，特别是雌激素生物合成。因此，这些发现的一个推论是，似乎合理地提出，雌激素依赖性疾病，如子宫内膜异位症，可能受益于卵泡刺激素在卵巢的作用抑制
We previously described a negative allosteric modulator (NAM) of FSHR (ADX61623) that blocked FSH-induced cAMP and progesterone production but did not block estradiol production. That FSHR NAM did not affect FSH-induced preovulatory follicle development as evidenced by the lack of an effect on the number of FSH-dependent oocytes found in the ampullae following ovulation with hCG. A goal is the development of a nonsteroidal contraceptive. Toward this end, a high throughput screen using human FSHR identified an additional nonsteroidal small molecule (ADX68692). Although ADX68692 behaved like ADX61623 in inhibiting production of cAMP and progesterone, it also inhibited FSH-induced estradiol in an in vitro rat granulosa primary cell culture bioassay. When immature, noncycling female rats were injected subcutaneously or by oral dosing prior to exogenous FSH administration, it was found that ADX68692 decreased the number of oocytes recovered from the ampullae. The estrous cycles of mature female rats were disrupted by administration by oral gavage of 25 mg/kg and 10 mg/kg ADX68692. In the highest dose tested (25 mg/kg), 55% of animals cohabited with mature males had implantation sites compared to 33% in the 10 mg/kg group and 77% in the control group. A surprising finding was that a structural analog ADX68693, while effectively blocking progesterone production with similar efficacy as ADX68692, did not block estrogen production and despite better oral availability did not decrease the number of oocytes found in the ampullae even when used at 100 mg/kg. These data demonstrate that because of biased antagonism of the FSHR, nonsteroidal contraception requires that both arms of the FSHR steroidogenic pathway must be effectively blocked, particularly estrogen biosynthesis. Thus, a corollary to these findings is that it seems reasonable to propose that the estrogen-dependent diseases such as endometriosis may benefit from inhibition of FSH action at the ovary