Addex Therapeutics, a leading company pioneering allosteric modulation-based drug discovery and development, announced that it has been awarded a CHF 666,240 grant from the Swiss Commission for Technology and Innovation (CTI) to advance the characterization of allosteric modulator therapeutics for neurodegenerative and psychiatric diseases.
Addex will collaborate with the group of Prof. Ron Stoop at the Center for Psychiatric Neuroscience (CNP), part of Lausanne University Hospital (CHUV) and Lausanne University (UNIL).
The objective of the project is the characterization and optimization of potent and selective allosteric modulators targeting metabotropic glutamate receptors subtypes 4 and 7. Effect of drug candidates will be assessed in electrophysiological studies using optogenetic approaches, targeting specifically the thalamus-to-amygdala synapse, a connection central to fear learning and extinction. Data from the project will contribute to the understanding of the role played by these glutamate receptors in anxiety disorders and help the selection of the best candidate compounds for clinical development.
"We are thrilled to extend our collaboration with Addex, a world leader in allosteric modulator discovery, and to help advance these two exciting neuroscience programs" commented Prof. Ron Stoop, Center for Psychiatric Neurosciences.
"Using our optogenetic approaches to test Addex proprietary compounds will generate essential information on their potential to affect neurotransmission in the amygdala, a structure of the limbic system involved in the processing of emotional responses and emotional memory. We expect to identify key mechanisms involving mGlu4 and mGlu7 receptors in these processes, which are imbalanced in an important number of psychiatric diseases."
Addex has identified a number of novel, selective, orally available mGluR4 positive allosteric modulators (PAMs), which have demonstrated efficacy in several different rodent models of Parkinson's disease, anxiety and most recently in the industry standard neuroinflammation model of multiple sclerosis, the Relapsing-Remitting Experimental Allergic Encephalomyelitis (RR-EAE) model. Similarly, the Company has identified unique mGluR7 negative allosteric modulators (NAMs) which have been shown to be efficacious in animal models of anxiety.
"We are delighted to receive this grant award from the Swiss Government. The use of allosteric modulators targeting mGlu4 and mGlu7 receptors offers a more precise way to regulate brain function in a number of disease areas where there is a high unmet medical need," explained Dr. Robert Lütjens, head of discovery at Addex.
"Accessing cutting edge technologies such as optogenetics by collaborating with the world class academic lab of Prof Ron Stoop (CHUV-UNIL) will significantly improve our scientific understanding and help advance our drug candidates."
"Following the recent signing of an agreement with Pierre Fabre Pharmaceuticals to advance our mGluR3 programme, this is an important step forward for our mGluR4 and mGluR7 programmes," commented Tim Dyer, CEO at Addex. "While we continue to focus on advancing dipraglurant in PD-LID and dystonia, the depth of Addex pipeline and its potential should not be forgotten."
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 (DCs). Emerging data implicate mGluR4 in multiple indications such as multiple sclerosis, Parkinson's disease, anxiety, neuropathic and inflammatory pain, schizophrenia, autism and diabetes.
The mGluR7 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.