Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: Evidence for its ability to support follicular development and ovulation

Sriraman, Venkataraman; Denis, Deborah; Matos, Daniel De; Yu, Hong; Palmer, Stephen; Nataraja, Selvaraj

doi:10.1016/j.bcp.2014.02.023

Cited by 32 publications

(33 citation statements)

References 35 publications

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“…Therefore, in order to develop drugs targeted to rescue the function of the receptor, a thorough understanding of the epitopes crucial for FSH–FSHR interaction is a must. In recent times, several small molecule FSHR agonists, which can be orally administered like Org 214444-0 ( 80 ), FSHR allosteric modulators like Compound 5 ( 81 ) have been developed, which can be administered to patients for ovulation induction. Pharmacoperones (pharmacological chaperones that assist in folding and routing of mutant receptors to the cell surface) like Org 41841 have been shown to rescue the function of the A 189 V FSHR mutant, which was trapped intracellularly and hence exhibited low-cell surface FSHR expression ( 82 ).…”

Section: Discussionmentioning

confidence: 99%

Role of the Extracellular and Intracellular Loops of Follicle-Stimulating Hormone Receptor in Its Function

Banerjee

Mahale

2015

Front. Endocrinol.

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Follicle-stimulating hormone receptor (FSHR) is a leucine-rich repeat containing class A G-protein coupled receptor belonging to the subfamily of glycoprotein hormone receptors (GPHRs), which includes luteinizing hormone/choriogonadotropin receptor (LH/CGR) and thyroid-stimulating hormone receptor. Its cognate ligand, follicle-stimulating hormone binds to, and activates FSHR expressed on the surface of granulosa cells of the ovary, in females, and Sertoli cells of the testis, in males, to bring about folliculogenesis and spermatogenesis, respectively. FSHR contains a large extracellular domain (ECD) consisting of leucine-rich repeats at the N-terminal end and a hinge region at the C-terminus that connects the ECD to the membrane spanning transmembrane domain (TMD). The TMD consists of seven α-helices that are connected to each other by means of three extracellular loops (ELs) and three intracellular loops (ILs) and ends in a short-cytoplasmic tail. It is well established that the ECD is the primary hormone binding domain, whereas the TMD is the signal transducing domain. However, several studies on the ELs and ILs employing site directed mutagenesis, generation of chimeric receptors and in vitro characterization of naturally occurring mutations have proven their indispensable role in FSHR function. Their role in every phase of the life cycle of the receptor like post translational modifications, cell surface trafficking, hormone binding, activation of downstream signaling, receptor phosphorylation, hormone–receptor internalization, and recycling of hormone–receptor complex have been documented. Mutations in the loops causing dysregulation of these processes lead to pathophysiological conditions. In other GPHRs as well, the loops have been convincingly shown to contribute to various aspects of receptor function. This review article attempts to summarize the extensive contributions of FSHR loops and C-terminal tail to its function.

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Section: Discussionmentioning

confidence: 99%

Role of the Extracellular and Intracellular Loops of Follicle-Stimulating Hormone Receptor in Its Function

Banerjee

Mahale

2015

Front. Endocrinol.

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“…Indeed, some TDZs are able to stimulate FSH-induced signaling in the absence of FSH and are able to induce folliculogenesis in immature rats. Despite such promising results, these compounds never reached the market due to unfavorable pharmacokinetic parameters [186]. Other compounds from the TDZ series showed the ability to switch FSHR coupling from Gα s to Gα i without the functional consequences for reproduction being clarified to date [187].…”

Section: Future Perspectivesmentioning

confidence: 99%

Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles

Santi

Crépieux

Reiter

et al. 2020

JCM

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Background: Human reproduction is regulated by the combined action of the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH) on the gonads. Although FSH is largely used in female reproduction, in particular in women attending assisted reproductive techniques to stimulate multi-follicular growth, its efficacy in men with idiopathic infertility is not clearly demonstrated. Indeed, whether FSH administration improves fertility in patients with hypogonadotropic hypogonadism, the therapeutic benefit in men presenting alterations in sperm production despite normal FSH serum levels is still unclear. In the present review, we evaluate the potential pharmacological benefits of FSH administration in clinical practice. Methods: This is a narrative review, describing the FSH physiological role in spermatogenesis and its potential therapeutic action in men. Results: The FSH role on male fertility is reviewed starting from the physiological control of spermatogenesis, throughout its mechanism of action in Sertoli cells, the genetic regulation of its action on spermatogenesis, until the therapeutic options available to improve sperm production. Conclusion: FSH administration in infertile men has potential benefits, although its action should be considered by evaluating its synergic action with testosterone, and well-controlled, powerful trials are required. Prospective studies and new compounds could be developed in the near future.

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“…Several thiazolidinones demonstrated efficacy in rat granulosa cells and induced folliculogenesis in vivo in immature rats. However, further developments were hampered by unfavorable pharmacokinetics parameters [147]. Benzamides also showed selective PAM activity for FSHR compared to TSHR and LHCGR [148].…”

Section: Future Directions In the Control Of Fshr Signalingmentioning

confidence: 99%

FSH for the Treatment of Male Infertility

Casarini

Crépieux

Reiter

et al. 2020

IJMS

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Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.

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Investigation of a thiazolidinone derivative as an allosteric modulator of follicle stimulating hormone receptor: Evidence for its ability to support follicular development and ovulation

Cited by 32 publications

References 35 publications

Role of the Extracellular and Intracellular Loops of Follicle-Stimulating Hormone Receptor in Its Function

Role of the Extracellular and Intracellular Loops of Follicle-Stimulating Hormone Receptor in Its Function

Follicle-Stimulating Hormone (FSH) Action on Spermatogenesis: A Focus on Physiological and Therapeutic Roles

FSH for the Treatment of Male Infertility

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