Abstract

Chronic pain is a public health problem as current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited due to its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) α₂δ subunit. HSK16149 inhibited [³H]gabapentin binding to the α₂δ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 h post-administration at 30 mg/kg, while the efficacy of pregabalin lasted only for 12 h at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, while in the rotarod test, the MEDs of HSK16149 and pregabalin were 100 mg/kg and 30 mg/kg, respectively. These finding indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC α₂δ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain.

Significance Statement As a novel potent ligand of VGCC α₂δ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.