Addex mGluR4 PAM improves Parkinsonian symptoms in pre-clinical models

16th July 2012 (Last Updated July 16th, 2012 18:30)

Addex Therapeutics has announced the positive pre-clinical efficacy data of metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator (PAM) in Parkinson's disease pre-clinical models.

Addex Therapeutics has announced the positive pre-clinical efficacy data of metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulator (PAM) in Parkinson's disease pre-clinical models.

The research conducted in collaboration with Merck showed that ADX88178, has the potential to improve the symptoms of Parkinson's disease as shown in two rodent models of dopamine depletion. The drug is an mGluR4 selective that is orally available and brain penetrant small molecule.

ADX88178, a potent allosteric modulator of mGluR4 that shows selectivity against other metabotropic glutamate receptors, was found to enhance glutamate-mediated activation of human and rat mGluR4 with EC50 values of 3.5nM and 9.1nM respectively.

“This is another example of the power of Addex's platform to identify and develop oral, highly selective, brain penetrant compounds with adequate drug-like properties.”

Addex chief scientific officer Graham Dixon said research showed that increasing mGluR4 activity could normalise the aberrant synaptic transmission resulting from dopamine depletion and restore normal activity in the brain circuits that control movement.

"The allosteric modulation approach enables modulation of mGluR4 with exquisite selectivity and our research provides compelling evidence and validation for mGluR4 activation for the treatment of Parkinson's disease and a host of other indications through a non-dopaminergic approach," Dixon added.

Oral administration of ADX88178, which was shown to reverse haloperidol-induced catalepsy in rats at 3mg/kg and 10mg/kg, was associated with high bioavailability and was able to readily penetrate into the brain.

The combination of ADX88178 with a low dose of L-DOPA allows dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats.

According to the company, a similar synergistic effect was also demonstrated with Quinpirole, the Dopamine D2 agonist.

Addex mGluR4 programme head Sylvain Celanire said: "This is another example of the power of Addex's platform to identify and develop oral, highly selective, brain penetrant compounds with adequate drug-like properties where others faced flat structure-activity relationship (SAR) and a poor developability profile."