期刊
BIOCHEMICAL PHARMACOLOGY
卷 89, 期 2, 页码 266-275出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2014.02.023
关键词
FSH receptor; FSH signalling; Follicular development; Ovulation; Glycoprotein hormone receptors; FSHR agonist
FSH signalling through its cognate receptor is critical for follicular development and ovulation. An earlier study had documented thiazolidinone derivatives to activate FSH receptor expressed in CHO cells and rat granulosa cells; however development of this compound for clinical use was halted for unobvious reasons. The objective of the current study is to extend the previous investigations in detail on the ability of thiazolidinone derivative (henceforth referred to as Compound 5) to activate FSH signalling and learn the barriers that preclude development of this derivative for clinical purposes. Our results demonstrate that the Compound 5 in a dose-dependent manner stimulated CAMP production, activated AKT and ERK signalling pathways and induced estradiol production in cultured rat granulosa cells. Compound 5 also caused dose-dependent increase in estradiol production from human granulosa cells. In increasingly more complex in vitro systems, Compound 5 was able to induce the expansion of mouse cumulus-oocyte-complex and support in vitro development of mouse preantral follicle to preovulatory stage and release of oocyte from the follicle. In vivo, the compound stimulated preovulatory follicular development and ovulation in immature rats. Pharmacokinetic and safety investigations reveal poor oral availability and genotoxcity. Together, our results document Compound 5 to act as a FSHR allosteric modulator but have poor pharmacological properties for development of an oral FSH receptor modulator. (C) 2014 Elsevier Inc. All rights reserved.
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