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Discovery of orally efficacious tetracyclic metabotropic glutamate receptor 1 (mGluR1) antagonists for the treatment of chronic pain.

Metabotropic glutamate receptor 1 (mGluR1) plays important roles in the neurotransmission and pathogenesis of several neurological disorders, including chronic pain. Antagonists of mGlur1 are suggested to be useful for the treatment of pain. Herein, we report the discovery of a novel series of tetracyclic mGluR1 antagonists, such as 23c and 23e, with oral efficacy of ED50 of 8 and 5.1 mg/kg, respectively, in rat spinal nerve ligation neuropathic pain model.