Pharmacological characterization of MRZ-8676, a novel negative allosteric modulator of subtype 5 metabotropic glutamate receptors (mGluR5): focus on L: -DOPA-induced dyskinesia.

摘要

Subtype 5 metabotropic glutamate receptors (mGluR5) are abundant in the basal ganglia, amygdala, septum, hippocampus, peripheral sensory neurones and dorsal horn of the spinal cord. Thus, mGluR5 has been implicated in central processes underlying movement control, emotion, learning, and nociception. Different negative allosteric modulators (NAMs) of mGluR5 were repeatedly shown to be efficacious in models of L: -DOPA-induced dyskinesia (LID), anxiety, and some forms of pain. MRZ-8676 (6,6-dimethyl-2-phenylethynyl-7,8-dihydro-6H-quinolin-5-one) is a novel proprietary, selective, orally bioavailable mGluR5 NAM. MRZ-8676 (8.33, 25 and 75 mg/kg) showed a high efficacy in the rat model of LID, with the maximal effect size reaching ~80%. The antidyskinetic effects of MRZ-8676 (75 mg/kg) did not show tolerance as assessed after repetitive (6 days) treatment. MRZ-8676 (25 or 75 mg/kg) demonstrated moderate efficacy in two rat models of anxiety-contextual fear conditioning and the elevated plus maze. MRZ-8676 (25 mg/kg) was also effective in the formalin test, a rat model of persistent pain. The efficacious doses of MRZ-8676 did not produce any detrimental effects on motor performance of rats as determined by means of automated open field and rotarod. However, high doses of MRZ-8676 (75 or 150 mg/kg) disrupted learning in an aversive learning paradigm of the contextual fear conditioning test. In conclusion, MRZ-8676 is a new investigational agent with an efficacy profile similar to the widely published reference mGluR5 NAMs. The drug was demonstrated to possess a superior antidyskinetic efficacy with a sufficient therapeutic window. MRZ-8676 has also therapeutic potential as an anxiolytic and analgesic drug.