Geneva, Switzerland, December 9, 2015 - Addex Therapeutics (SIX: ADXN), a leading company pioneering allosteric modulation-based drug discovery and development, announced today the publication of new scientific findings in the peer reviewed journal Neuropharmacology. These studies were carried out in collaboration with the group of Professor Ursula Grohmann, University of Perugia, Italy, and address the role of metabotropic glutamate receptor 4 (mGluR4) in regulating dendritic cells and immune responses involved in multiple sclerosis.
ADX88178, a selective mGluR4 positive allosteric modulator (PAM) discovered by Addex, was tested in the mouse relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) model, commonly used to test the therapeutic potential of compounds for multiple sclerosis. The administration of ADX88178 converted the disease into a form of mild neuro-inflammation that remained stable for over two months after discontinuing drug treatment. The studies further investigated the molecular pathways involved in the secretion of cytokines by dendritic cells, a cell type expressing mGlu4 receptors and playing a key role in the development of immune responses. In particular, the observed increase in production of tolerogenic IL-10 and TGF-beta were found to rely on a G protein-independent pathway involving specific kinases (PI3K, Src) and indoleamine 2,3-dioxygenase 1 (IDO1).
“Our findings demonstrate the central role played by mGlu4 receptors in the regulation of immune response mediated through dendritic cells” commented Professor Grohmann. “The effects observed with Addex’ highly selective and potent mGluR4 PAM, which activates long-lived regulatory pathways, suggest that such a compound could be therapeutically exploited in chronic autoimmune diseases”.
“These new findings are exciting as IDO1 plays a critical role in several inflammatory/autoimmune conditions,” commented Dr Robert Lütjens, Head of Discovery at Addex. “These results consolidate the validation of our mGluR4 approach for multiple sclerosis and open up additional opportunities for mGluR4 PAMs as a potential treatment for rheumatoid arthritis and inflammatory bowel diseases”.
“We are very pleased with our ongoing collaboration with Professor Grohmann’s group and the data generated in their specialized models,” commented Tim Dyer, CEO at Addex. “This collaboration is a great example of how we are able to advance the understanding of the role of mGluRs and generate significant value in our portfolio of allosteric modulator drug candidates.”
Volpi et al., Neuropharmacology 2015 Oct30; 102:59-71
About mGlu4 receptor
The mGluR4 belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Galphai/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in neurotransmitter release from presynaptic terminals. The mGluR4 is uniquely distributed in key brain regions involved in multiple CNS disorders. In particular, mGluR4 is abundant in striato-pallidal synapses within the basal ganglia circuitry a key area implicated in movement disorders, like Parkinson’s disease. In the immune system mGluR4 has been found on dendritic cells. Emerging data implicate mGluR4 in multiple indications such as multiple sclerosis, Parkinson’s disease, anxiety, neuropathic and inflammatory pain, schizophrenia, autism and diabetes.
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 IIb/III for PD-LID. In parallel, dipraglurant’s therapeutic use in dystonia is being investigated. Addex second clinical program, ADX71149 (mGluR2 positive allosteric modulator or PAM) is being developed in collaboration with Janssen Pharmaceuticals, Inc for Epilepsy. Addex also has several preclinical programs including: ADX71441 (GABAB receptor PAM) which has received regulatory approval to start Phase I and is being investigated for therapeutic use in Charcot-Marie-Tooth (Type 1A) disease, alcohol use disorder and nicotine dependence; mGluR4PAM for drug abuse and dependence, Parkinson’s disease and other neurodegenerative diseases; mGluR2NAM for treatment resistant depression and cognitive deficits; mGluR7NAM for psychosomatic disorders, TrkBPAM for neurodegenerative disorders; and GLP1PAM for type 2 diabetes. 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.
