Addex mGluR4 and mGluR7 Programs Demonstrate Potential in Preclinical Models of Neurodegenerative and Psychiatric Diseases
Geneva, Switzerland, 13 June 2016 – Addex Therapeutics (SIX:ADXN), announced today the successful completion of the first part of a project funded by the Swiss Commission for Technology and Innovation (CTI) to characterize Addex’ mGlu4 and mGlu7 receptor allosteric modulators in models of neurodegenerative and psychiatric diseases. The program was conducted in collaboration with the Center for Psychiatric Neuroscience (CNP) at the Centre Hospitalier Universitaire Vaudois (CHUV), and the Laboratory for the Study of Neurodegenerative Diseases (LEN) at Ecole Polytechnique Fédérale de Lausanne (EPFL).
ADX88178, an mGluR4 positive allosteric modulator (PAM), was tested in a preclinical model of Parkinson’s disease where rats were unilaterally injected in the substantia nigra with an adeno-associated viral vector encoding human alpha-synuclein which induces motor impairments, dopamine loss and important features of the idiopathic disease, including α-synuclein accumulation and degeneration of nigral dopaminergic neurons. ADX88178 administered chronically (60 mg/kg subcutaneously for 10 weeks) was able to induce a reduction in the motor impairments observed in the model, but without significantly affecting the progression of the observed neurodegeneration.
The effect of ADX71743, an mGluR7 negative allosteric modulator (NAM) and ADX88178 were tested on electrophysiological slice recordings at the thalamus-to-amygdala synapses. The experiments demonstrated that ADX71743 and ADX88178 were able to impact the excitatory neurotransmission in the amygdala. This is an important discovery as emotional stimuli get relayed through auditory thalamus into amygdala which is an important pathway involved in the establishment of fear. These findings provide a mechanistic explanation of the anxiolytic effects previously observed in preclinical models of anxiety with these compounds (Kalinichev et al. 2013). A peer reviewed publication synthetizing all data obtained in these studies is in preparation.
Following the successful completion of the planned studies, the team has recently been awarded a second grant by CTI of CHF660’240 to support the continued characterization of mGluR4 and mGluR7 compounds in fear conditioning and reward models using combined electrophysiological and optogenetic methods.
“The results of these studies demonstrate the potential effect our unique molecules may have on the processes underlying Parkinson’s disease and on extinction of learned fear, a central process believed to be affected in Post-Traumatic Stress Syndrome.", commented Dr Robert Lütjens, Head of Discovery at Addex. "With the continued support of CTI and our collaboration partners at CHUV and EPFL, we are now building on these data to further advance our understanding of the important roles played by mGlu4 and mGlu7 receptors in neurological and psychiatric disorders.”
The mGlu4 receptor belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gαi/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 (DCs). Emerging data implicate mGluR4 in multiple indications such as multiple sclerosis, Parkinson’s disease, anxiety, neuropathic and inflammatory pain, schizophrenia and diabetes.
The mGlu7 receptor is the most highly conserved of all mGluR subtypes, exhibiting the widest distribution in the brain. It is localized pre-synaptically at a broad range of glutamatergic and GABAergic synapses and is thought to be one of the most important mGluR subtypes in regulating CNS function. Preclinical data suggest that mGluR7 antagonism could alleviate stress-related anxiety and depressive symptoms and deficits in amygdala-dependent behaviors (fear response and conditioned taste aversion). These data are consistent with the abundant localization of mGluR7 in brain regions involved in the control of fear and emotion.
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), alcohol use disorder, cocaine 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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