New Tricyclic γ‑Aminobutyric Acid Analogue HSK16149: A Ca2+ Channel α2‑δ Ligand for Treating Neuropathic Pain.

Pregabalin and gabapentin are currently first-line treatments for neuropathic pain, but common adverse effects such as dizziness and somnolence frequently lead to treatment discontinuation. To find new drugs that mitigate CNS adverse effects while maintaining good efficacy, more than 50 tricyclic GABA derivative compounds were screened and HSK16149 (compound 7) was selected in the present study. Further evaluation revealed that HSK16149 had a good potent binding affinity to the Ca2+ channel α2-δ subunits (IC50 = 3.96 nM) and an AUC of 13,200 ng·h/mL which was obviously higher than the control drug pregabalin. HSK16149 also demonstrated superior antihypersensitivity or antiallodynic/hyperalgesic effects compared to the commonly used pregabalin as the control and has the potential to minimize CNS side effects with good tolerability. Based on its exceptional preclinical characteristics, HSK16149 was chosen for further development to provide a more effective and safer drug for patients enduring neuropathic pain.