Addex Announces the Publication of Positive Data on the Efficacy of mGluR4 Positive Allosteric Modulator in Parkinson …

PLAN-LES-OUATES GENEVA, SWITZERLAND--(Marketwire -07/16/12)-

Addex Therapeutics / Addex Announces the Publication of Positive Data on the Efficacy of mGluR4 Positive Allosteric Modulator in Parkinson's Disease Pre-Clinical Models . Processed and transmitted by Thomson Reuters ONE. The issuer is solely responsible for the content of this announcement.

Seminal Research Provides Greater Insight into the Role of Selective mGluR4 Modulation on Motor Symptoms in Parkinson's disease

Geneva, Switzerland, 16 July 2012 - Addex Therapeutics (SIX:ADXN), a leading company pioneering allosteric modulation-based oral small molecule drug discovery and development, announced today the publication of positive pre- clinical efficacy data on its novel, highly selective oral small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor 4 (mGluR4), and its role in Parkinson's disease. The results were published in the Journal of Pharmacology and Experimental Therapeutics (JPET) on 11 July 2012 as DOI:10.1124/jpet.112.196063. The researchers report the discovery of ADX88178, a novel, potent, brain penetrant and selective mGluR4 PAM, with drug- like properties, to explore the therapeutic potential of mGluR4 modulation in disease models. The research was conducted in collaboration with Merck & Co.

"There continues to be a significant need for new approaches to treat Parkinson's disease. Research shows that increasing mGluR4 activity could normalize the aberrant synaptic transmission resulting from dopamine depletion and restore normal activity in the brain circuits that control movement," explained Dr. Graham Dixon, Chief Scientific Officer at Addex. "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."

Study Details

The publication entitled, "A potent and selective mGluR4 positive allosteric modulator improves movement in rodent models of Parkinson's disease" reported that ADX88178, an mGluR4 selective, potent, orally available and brain penetrant small molecule, has the potential to ameliorate the Parkinsonian symptoms as shown in two rodent models of dopamine depletion. ADX88178 was found to enhance glutamate-mediated activation of human and rat mGluR4 with EC(50) values of 3.5 and 9.1 nM respectively. ADX88178 is a potent allosteric modulator of mGluR4 that shows excellent selectivity against other metabotropic glutamate receptors. Oral administration of ADX88178 in rats was associated with high bioavailability and was able to readily penetrate into the brain. ADX88178 was shown to reverse haloperidol-induced catalepsy in rats at 3 and 10 mg/kg. More importantly, the combination of ADX88178 (3, 10 and 30 mg/kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats. Similar synergistic effect was also demonstrated with Dopamine D2 agonist, Quinpirole. In addition, co-administration of ADX88178 (10 mg/kg, p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent with an L-DOPA sparing action that may prove to be therapeutically useful for the management of motor symptoms of PD. ADX88178 is an invaluable proof of concept candidate in that it appears to be the most potent of the mGluR4 PAM molecules reported to date, and also has a greater window of selectivity against mGluRs, as well as other non-GPCR targets.

"This is another example of the power of Addex' 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" commented Sylvain Celanire, Head of the mGluR4 program at Addex. "We are excited by these preclinical results and are looking forward to rapidly advancing our lead molecule into the clinic"

About mGluR4

The metabotropic glutamate receptor 4 (mGluR4) belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gi/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in transmitter release from presynaptic terminals. MGluR4 is currently receiving much attention based primarily upon its unique distribution in key brain region involved in many CNS disorders. In particular, mGluR4 is abundant in striato-pallidal synapses within the basal ganglia circuitry a key area for motor control. MGluR4 PAM is therefore emerging as a promising target for the treatment of motor (and non motor) symptoms as well as a disease-modifying agent in Parkinson's disease through a non- dopaminergic approach. In addition to the search for novel drugs that relieve motor symptoms of Parkinsonism, attenuating the ongoing degeneration of nigrostriatal neurons is also of increasing interest. Orthosteric mGluR4 agonist L-AP4 has demonstrated neuroprotective effects in a 6-OHDA rodent model of PD and first discovered allosteric potentiator (-)-PHCCC reduced nigrostriatal degeneration in mice treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). Those studies provide preclinical evidence suggesting that mGluR4 activators constitute a strong approach not only for symptomatic treatments of PD, but also potentially as disease modifiers.

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Addex Announces the Publication of Positive Data on the Efficacy of mGluR4 Positive Allosteric Modulator in Parkinson ...