Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.