click to enlarge Allosteric modulators bind, generally in the cell membrane, via a non-competitive mechanism that exerts its effects on signal transduction primarily after binding by the endogenous ligand at the active site. (Source: Addex Pharmaceuticals)

Glutamate is a critical neurotransmitter that is involved in a multitude of biological functions and disease processes. Despite its rich therapeutic potential, the glutamatergic system has historically been a challenge for drug discoverers because chemistry allowing selective modulation of glutamate receptors was limited. The discovery of selective drug-like allosteric modulators has opened up the possibility of drugging the glutamatergic system, specifically the eight receptor subtypes in the metabotropic glutamate receptor (mGluR) family.  Metabotropic glutamate receptor 5 (mGluR5) is found in regions of the brain considered to be key control points in the neuronal movement circuits. These circuits are thought to be responsible for the abnormal signaling by the neurotransmitter glutamate. Along with disruptions in dopaminergic signaling, perturbations in glutamate signaling are believed to be an underlying cause of movement disorders like Parkinson’s disease. As such, inhibiting mGluR5 could act to re-establish normal movement via a non-dopaminergic mechanism.

Evidence indicates that mGluR5 inhibition may prove to be a valuable new therapeutic strategy for treating Parkinson’s disease (PD) and Parkinson’s disease levodopa-induced dyskinesia (PD-LID). Preclinical research in rodent and primate models suggest that mGluR5 inhibition could treat PD symptoms¹ and alleviate PD-LID². In 2008, AFQ056 (an mGluR5 inhibitor from Novartis) achieved Phase 2a clinical proof of concept in PD-LID.³ These clinical and preclinical data also provide hints that mGluR5 inhibition may have the potential to be a dopamine sparing drug. Additional preclinical findings suggest that mGluR5 inhibitors may be neuroprotective and, therefore, have the potential to slow disease progression.⁴ 

ADX48621, an mGluR5 NAM being developed by Addex Pharmaceuticals has shown efficacy in a non-human primate model of PD-LID.⁵ These data suggest that ADX48621 is differentiated and shows considerable efficacy on both components of dyskinesia–chorea and dystonia.

Indeed, we believe ADX48621 is the first and only product to have been reported to have efficacy on dystonia in this model of PD-LID.

ADX48621 has completed Phase 1 testing and is initiating one study for ADX48621 in PD-LID patients and a second study for ADX48621 in patients with dystonia.

References
1. Ossowska K, Konieczny J, Wolfarth S, Pilc A. MTEP, a new selective antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), produces antiparkinsonian-like effects in rats. Neuropharmacology. 2005; 49(4):447.
2. Movement Disorder Society Congress 2008 abstract.
3. Novartis Clinical Trial Results Database. http://www.novctrd.com. Accessed on September 27, 2010.
4. Neurobiology of Disease, Volume 22, Issue 1, April 2006, Pages 1-9
5. Addex press release and presentation.