Addex Collaborators Published New Data Supporting the Role of Negative Allosteric Modulators of Follicle Stimulating Hormone and Luteinizing Hormone Receptors in Reproductive Health
Geneva, Switzerland, 20 September 2016 – Addex Therapeutics (SIX: ADXN) announced today the publication of new scientific findings that help unravel the mode of action of dual follicle stimulating hormone receptor (FSHR) and luteinizing hormone/chorionic gonadotropin hormone receptor (LH/CGR) negative allosteric modulators (NAMs).
The results show that both ADX68692 and ADX68693, while being NAMs of FSHR, also strongly antagonize LH/CGR signaling in murine Leydig tumor cell line (mLTC-1) and in rat primary Leydig cells. This finding is of great importance given the involvement of both FSHR and LH/CGR in reproduction and their co-expression within granulosa cells at specific stages of the female reproductive cycle.
“Having access to Addex unique allosteric modulator pharmacological tools to interrogate how receptors transmit their signal intracellularly has proven an invaluable opportunity to understand better the roles FSH and LH/CGR receptors play in controlling reproduction”, said Professor Eric Reiter, of the French National Institute of Agricultural Research, University of Tours, France.
The physiological effects of FSH and LH on the ovary are characterized by the stimulation of the production of estradiol and progesterone, which play key roles in ovarian function and control of the reproductive cycle. A significant inhibition of testosterone production by both ADX68692 and ADX68693 was observed in both cell types, whereas progesterone production was only inhibited by ADX68693 in rat primary Leydig cells. In addition, while ADX68693 totally abolished testosterone production, ADX68692 had only a partial effect in both mLTC-1 and rat primary Leydig cells, suggesting differential effects of the two NAMs on LH/CGR dependent pathways controlling steroidogenesis. These finding support the results previously obtained from the collaboration with Professor James Dias, University of Albany, showing that while ADX68692 blocked FSHR-promoted cAMP, progesterone and estradiol production, ADX68693 inhibited cAMP and progesterone with no effect on estradiol production.
ADX68692 and ADX68693 were discovered at Addex and their pharmacological profile as NAMs at the FSHR has been extensively examined in collaboration with Professor James Dias (Dias et al, 2014). These new finding, published in Molecular and Cellular Endocrinology1 by the group of Professor Eric Reiter at the University of Tours, France, show their effect on the LH/CGR and their differential effect on intracellular signalling.
Taken together, these findings, illustrate the complexity of signaling pathways controlling FSHR and LH/CGR mediated steroidogenesis, and suggest differential implication of G protein and beta-arrestin mediated intracellular signaling. ADX68692 and ADX68693 were identified as biased NAMs at the LH/CGR in addition to the FSHR. These pharmacological characteristics are important to consider for potential therapeutic applications.
“We thank the group of Professor Eric Reiter for these data and publication which show how versatile allosteric modulators can be in activating or inhibiting specific intracellular signaling of a therapeutic target”, said Robert Lütjens, Head of Discovery of Addex, “further demonstrating the potential advantage of an allosteric drug discovery approach to address drug targets, a dimension which we have integrated in our small molecule allosteric drug discovery platform.”
“While we focus on advancing our clinical stage portfolio, including dipraglurant in Parkinson’s disease levodopa-induced dyskinesia and dystonia, these new data are a great example of how we are adding value to our preclinical programs through collaboration with academic institutions”, commented Tim Dyer CEO of Addex.
1. M.A. Ayoub et al, Molecular and Cellular Endocrinology, 436 (2016) 10-22
2. J.A. Dias et al, Biology of reproduction, 90 (2014) 19
About Addex Therapeutics
Addex Therapeutics (www.addextherapeutics.com) is a biopharmaceutical company focused on the development of novel, orally available, small molecule allosteric modulators for neurological disorders. Addex lead drug candidate, dipraglurant (mGluR5 negative allosteric modulator or NAM) has successfully completed a phase IIa POC in Parkinson’s disease levodopa-induced dyskinesia (PD-LID), and is being prepared to enter phase III for PD-LID with support from the Michael J. Fox Foundation for Parkinson’s Research (MJFF). In parallel, dipraglurant’s therapeutic use in dystonia is being investigated with support from the Dystonia Medical Research Foundation (DMRF). Addex second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc for epilepsy. In addition, ADX71441 (GABAB receptor PAM) has received regulatory approval to start phase I and is being investigated for its therapeutic use in Charcot-Marie-Tooth Type 1A disease (CMT1A), cocaine and alcohol use disorder and nicotine dependence. Discovery programs include mGluR4PAM for neurodegenerative diseases, mGluR7NAM for psychosomatic disorders and TrkBPAM for neurodegenerative disorders which are being advanced in collaboration with the Universities of Lausanne and Geneva under the Swiss CTI grant program; and mGluR3PAM which is being advanced in collaboration with Pierre Fabre Pharmaceuticals. Allosteric modulators are an emerging class of small molecule drugs which have the potential to be more specific and confer significant therapeutic advantages over conventional "orthosteric" small molecule or biological drugs. Addex allosteric modulator drug discovery platform targets receptors and other proteins that are recognized as essential for therapeutic intervention – the Addex pipeline was generated from this pioneering allosteric modulator drug discovery platform.
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