Date: 2015-12-09
Type of information: Publication of results in a medical journal
phase: preclinical
Announcement: publication of results in Neuropharmacology
Company: Addex Therapeutics (Switzerland)
Product: ADX88178
Action
mechanism: mGluR4 positive allosteric modulator (PAM)
Disease:
Therapeutic area: Neurodegenerative diseases - CNS diseases
Country:
Trial details:
Latest
news: * On December 9, 2015, Addex Therapeutics announced the publication of new scientific findings in Neuropharmacology (Volpi et al., Neuropharmacology 2015 Oct30; 102:59-71). 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). * On 16 July 2012, Addex Therapeutics has announced the publication of positive pre-clinical efficacy data on its novel, highly selective oral small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor 4 (mGluR4), and its role in Parkinson\'s disease. The results were published in the Journal of Pharmacology and Experimental Therapeutics (JPET) on 11 July 2012. The researchers report the discovery of ADX88178, a novel, potent, brain penetrant and selective mGluR4 PAM, with drug-like properties, to explore the therapeutic potential of mGluR4 modulation in disease models. The research was conducted in collaboration with Merck & Co.
The publication entitled, "A potent and selective mGluR4 positive allosteric modulator improves movement in rodent models of Parkinson's disease" reported that ADX88178, an mGluR4 selective, potent, orally available and brain penetrant small molecule, has the potential to ameliorate the Parkinsonian symptoms as shown in two rodent models of dopamine depletion. ADX88178 was found to enhance glutamate-mediated activation of human and rat mGluR4 with EC50 values of 3.5 and 9.1 nM respectively. ADX88178 is a potent allosteric modulator of mGluR4 that shows excellent selectivity against other metabotropic glutamate receptors. Oral administration of ADX88178 in rats was associated with high bioavailability and was able to readily penetrate into the brain. ADX88178 was shown to reverse haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. More importantly, the combination of ADX88178 (3, 10 and 30 mg/kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats. Similar synergistic effect was also demonstrated with Dopamine D2 agonist, Quinpirole. In addition, co-administration of ADX88178 (10 mg/kg, p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent with an L-DOPA sparing action that may prove to be therapeutically useful for the management of motor symptoms of PD. ADX88178 is an invaluable proof of concept candidate in that it appears to be the most potent of the mGluR4 PAM molecules reported to date, and also has a greater window of selectivity against mGluRs, as well as other non-GPCR targets.
