Bowers C Y, Humphries J, Wasiak T, Folkers K, Reynolds G A, Reichert L E
Endocrinology. 1980 Mar;106(3):674-83. doi: 10.1210/endo-106-3-674.
A detailed study of the activity of LHRH analog antagonists has been made in four assay systems which measure inhibition of the action of LHRH on isolated rat pituitaries in vitro, inhibition of the release of the LH induced by LHRH in vivo in adult male rats and adult male chimpanzees, and inhibition of spontaneous ovulation in cycling female rats. Only a partial correlation was observed between the in vitro and in vivo assays. Currently, the most potent LHRH analog antagonists in the present study were based on a 1,2,3,6-tetra-substituted LHRH sequence. The analogs [D less than Glu1,DPhe2,DTrp3,DTrp6]-LHRH, Ac-[Pro1,DPhe2,DTrp3,DTrp6]LHRH and [(Glu-Pro)1, dphe2,DTrp3,DTrp6]LHRH completely inhibited spontaneous ovulation in cycling rats at a dosage of 200 microgram/rat, sc. The most potent inhibitors of ovulation were always very potent in vitro, but other analogs having identical in vitro activities had little or no antiovulatory activity even at substantially higher dosages. The analogs inhibited the action of LHRH in the rat more easily than in the chimpanzee. Twelve of 13 analogs at the analog to LHRH ratio of 100:1 significantly inhibited the LH response, while only 5 of 9 of these same analogs inhibited the LH response in the chimpanzee at the analog to LHRH ratio of 333:1. Only 1 of 8 analogs at a high dosage inhibited the binding of labeled LH to the gonadal LH receptor in vitro. The inability of the less polar (cyclopentane carboxylic acid) analogs to inhibit ovulation could be explained, at least partially, in terms of impaired absorption sc. Although the cyclopentane carboxylic acid analogs effectively inhibited the action of LHRH in vitro and, when given iv in vivo, they were not effective in blocking the LHRH-stimulated LH response in adult male rats when given sc, which is the mode of administration of the antiovulatory assay, suggesting the importance of the route of administration.
对促黄体生成素释放激素（LHRH）类似物拮抗剂的活性进行了详细研究，研究采用了四种测定系统，分别用于测量体外对LHRH作用于离体大鼠垂体的抑制作用、体内对成年雄性大鼠和成年雄性黑猩猩中LHRH诱导的促黄体生成素（LH）释放的抑制作用，以及对处于发情周期的雌性大鼠自发排卵的抑制作用。体外和体内测定之间仅观察到部分相关性。目前，本研究中最有效的LHRH类似物拮抗剂基于1,2,3,6 - 四取代的LHRH序列。类似物[D - 小于Glu1，DPhe2，DTrp3，DTrp6] - LHRH、Ac - [Pro1，DPhe2，DTrp3，DTrp6]LHRH和[(Glu - Pro)1，dphe2，DTrp3，DTrp6]LHRH以200微克/大鼠的皮下注射剂量完全抑制了处于发情周期大鼠的自发排卵。最有效的排卵抑制剂在体外总是非常有效，但其他具有相同体外活性的类似物即使在剂量大幅增加时也几乎没有或没有抗排卵活性。这些类似物对大鼠中LHRH作用的抑制比对黑猩猩更容易。13种类似物中有12种在类似物与LHRH比例为100:1时显著抑制LH反应，而在类似物与LHRH比例为333:1时，这些相同的类似物中只有9种中的5种抑制了黑猩猩的LH反应。8种类似物中只有1种在高剂量时在体外抑制了标记的LH与性腺LH受体的结合。极性较小的（环戊烷羧酸）类似物无法抑制排卵，这至少可以部分地用皮下吸收受损来解释。尽管环戊烷羧酸类似物在体外有效抑制LHRH的作用，并且在体内静脉注射时有效，但当以皮下注射给药（这是抗排卵测定的给药方式）时，它们在成年雄性大鼠中不能有效阻断LHRH刺激的LH反应，这表明给药途径的重要性。
