Subtype 5 metabotropic glutamate receptors (mGluR5) have been implicated in the control of movement, mood, cognition, and nociception. Correspondingly, different mGluR5 antagonists have been shown to alleviate L-DOPA-induced dyskinesia (LID), anxiety, and pain in experimental animals. A novel proprietary mGluR5 antagonist 6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one (MRZ-8676) having ~20 nM affinity to mGluR5, was tested in the rat models of LID, persistent pain, and anxiety. Effects of MRZ-8676 on motor performance and on learning were investigated. Presence of MRZ-8676 at target receptor in the brain was ascertained by measuring its extracellular concentrations and mGluR5 occupancy in vivo. MRZ-8676 had 20–25% bioavailability after oral treatment reaching Tmax at 2.9 h while T1/2 was 11.2 h. At 25 mg/kg p.o. Cmax was 348 ng/ml and AUC 2045 ng*h/ ml). In in vivo microdialysis experiments, pharmacologically effective p.o. doses of MRZ-8676 were found to achieve free brain concentrations sufficient to completely block mGluR5, i.e. above 100 nM. This finding was further confirmed by the results of the in vivo mGluR5 receptor occupancy study showing ED50 of ca. 5 mg/kg after i.p. administration. MRZ-8676 strongly and dose-dependently reduced abnormal involuntary movements in the 6-hydroxydopamine (6-OHDA) rat model of LID starting at 25 mg/kg. No tolerance of the antidyskinetic effects was observed upon subchronic (6-day) treatment with 75 mg/kg p.o. MRZ-8676 produced moderate anxiolytic effect in two rodent anxiety models, the contextual fear conditioning (at 25 mg/kg) and the elevated plus maze (25 mg/kg). At the same dose, MRZ-8676 also attenuated reaction to pain in the first phase of formalin test, the rat model of persistent pain induction. MRZ-8676 did not produce any detrimental effects on motor performance of rats as investigated rotarod test up to 150 mg/kg p.o. In the open field short lasting increase in locomotor activity was observed (25–150 mg/kg). However, MRZ-8676 dose dependently impaired learning in aversive learning paradigm of the contextual fear conditioning test reaching significance at 75 mg/kg which is above minima effective dose in tests for dyskinesia, pain or anxiety. Summing up, MRZ-8676 has clear-cut antidyskinetic properties with a sufficient therapeutic window. Moreover, it has anxiolytic and analgesic properties. Receptor occupancy and microdialysis studies indicate that the behavioural effects of MRZ-8676 are associated with blockade of mGluR5 in the brain. Moreover, preclinical rational and status of clinical trials with mGluR5 NAMs in Parkinson´s disease, Fragile X and gastroesophageal reflux will be presented.
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