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arXiv · 1808.00310

Profiling of FSHR Negative Allosteric Modulators on LH/CGR Reveals Biased Antagonism with Implications in Steroidogenesis

Mohammed Akli Ayoub·Romain Yvinec·Gwenhaël Jégot·James A. Dias·Sonia-Maria Poli·Anne Poupon·Pascale Crépieux·Eric Reiter
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Abstract

Biased signaling has recently emerged as an interesting mean to modulate the function of many G protein-coupled receptors (GPCRs). Previous studies reported two negative allosteric modulators (NAMs) of follicle-stimulating hormone receptor (FSHR), ADX68692 and ADX68693, with differential effects on FSHR-mediated steroidogenesis and ovulation. In this study, we attempted to pharmacologically profile these NAMs on the closely related luteinizing/chorionic gonadotropin hormone receptor (LH/CGR) with regards to its canonical Gs/cAMP pathway as well as \beta-arrestin recruitment in HEK293 cells. The NAMs effects on progesterone and testosterone production were also assessed in murine Leydig tumor cell line (mLTC-1). We found that both NAMs strongly antagonized LH/CGR signaling in both HEK293 and mLTC-1 cells. ADX68693 appeared more potent than ADX68692 to inhibit hCG-induced cAMP and \beta-arrestin 2 in HEK293 and mLTC-1 cells whereas no significant difference in their efficacy on hCG-promoted \beta-arrestin 2 recruitment. Interestingly, differential antagonism of the two NAMs on hCG-promoted steroidogenesis in mLTC-1 cells was observed with significant inhibition of testosterone but not progesterone production. These observations suggest biased effects of the two NAMs on LH/CGR-dependent pathways controlling steroidogenesis, which appeared to be different to that previously shown on FSHR. This also illustrates the complexity of signaling pathways controlling FSHR- and LH/CGR-mediated steroidogenesis, suggesting differential implication of cAMP and \beta-arrestins. Together, our data demonstrate that ADX68692 and ADX68693 are NAMs at the LH/CGR in addition to FSHR. These pharmacological characteristics are important to consider for potential contraceptive and therapeutic applications based on such compounds.

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Mohammed Akli Ayoub, Romain Yvinec, Gwenhaël Jégot, James A. Dias, Sonia-Maria Poli, Anne Poupon, Pascale Crépieux, Eric Reiter. 2018-08-01. Profiling of FSHR Negative Allosteric Modulators on LH/CGR Reveals Biased Antagonism with Implications in Steroidogenesis. https://doi.org/10.1016/j.mce.2016.07.013

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