The deal, worth up to $170m (€115.5m) will see the companies collaborate on the discovery and preclinical development of positive allosteric modulators (PAMs) that target the metabotropic glutamate receptor 4 (mGluR4) for use in the treatment of Parkinson's and other undisclosed indications. The deal includes an upfront payment of $3m with Addex being eligible for up to $106.5m if certain R&D and regulatory milestones are met. In addition, the company could receive a further $61m if further products are developed as well as undisclosed royalties on sales of any products that reach the market. Parkinson's disease is a brain disorder that effects over 5m people worldwide causing tremors, rigidity and slowness. While marketed medicines help ease the symptoms of the disease, there are currently no marketed therapies that slow disease progression. The disease occurs when neurons in an area of the brain known as the substantia nigra become impaired or die. These neurons produce the neurotransmitter dopamine which, among other things, enables smooth, coordinated muscle function and movement. Scientists at Merck provided the first evidence that mGluR4 activation has the potential to treat Parkinson's disease but have as yet struggled to develop specific mGluR4 activators. Addex' has made its name from developing small molecule drug candidates that target glutamate receptors and influence the shape of the main binding site by binding to receptors at sites distinct from the main site itself. This is known as allosteric modulation and allosteric agents can either have a positive or negative effect on the activity of the main receptor. "Addex has made exceptional progress in the area of mGlu receptor allosteric modulation," said Dr Darryle Schoepp, senior vice president and franchise head of Neuroscience at Merck Research Laboratories. "This partnership is key to us jointly establishing a leadership position in the promising area of mGluR4 receptor modulation for Parkinson's disease. Merck scientists are excited to work with Addex to extrapolate the full value of this novel mechanism for a range of neuroscience disorders." While the mechanism of mGluR4 activators is uncertain, research published in the journal Nature Reviews Neuroscience, co-authored by Dr Michael J. Marino of Merck Research Laboratories, suggests that they could work via two distinct mechanisms to alleviate the symptoms and potentially even slow the progression of the disease. It appears that mGluR4 activation can trigger a compensatory mechanism that may spare or activate dopamine receptor activators as well as having a neuroprotective effect that helps to preserve the brain's dopaminergic neurons. "We are proud to have established this collaboration with Merck because their researchers have helped to define the therapeutic potential of targeting mGluR4 to treat Parkinson's disease," said Vincent Mutel, CEO of Addex. "This is another important validation of our leadership in allosteric modulation."