Pharmacological, pharmacokinetics and safety profiles of DS-5565, a novel α₂δ ligand

DS-5565 is an analgesic drug that binds to the α₂δ subunit (α₂δ-1 and α₂δ-2) of voltage-dependent Ca²⁺ channels. The α₂δ-1 is the main target for the analgesic effect of α₂δ ligands. The contribution of the α₂δ-2 to the CNS side effects of α₂δ ligands still remains to be elucidated. To clarify the characteristics of DS-5565, we conducted the experiments using pregabalin (PGB) as a reference. The binding affinity and dissociation rate were investigated with rat α₂δ-1 and α₂δ-2 transfected cells. The analgesic effect was investigated with a von Frey test in streptozotocin (STZ)-induced diabetic rats. The CNS side effects were investigated with rota-rod performance (RR) and locomotor activity (LA) in rats. The plasma drug concentration was measured by LC–/INS;MS/MS. The binding affinities of DS-5565 for α₂δ-1 and α₂δ-2 were comparable to those of PGB. Interestingly DS-5565 showed a slower dissociation rate from α₂δ-1 than α₂δ-2, in particular α₂δ-1 compared to PGB. DS-5565 showed potent and sustained analgesic effects and the ED₅₀ was ca 2.5 mg/kg (ED₅₀ for PGB: 29.3 mg/kg). The plasma concentration of DS-5565 in the STZ rats, however, was about 65-fold less than PGB. DS-5565 inhibited RR (ID₅₀: 9.4 mg/kg) and LA (ID₅₀: 43.9 mg/kg) and the ratios ID₅₀/ED₅₀ (CNS safety margin) were ca 3.8 in RR and ca 18 in LA. The ratios for PGB were 0.4 and 3.9, respectively. DS-5565 has superior analgesic effects with a wider CNS safety margin relative to PGB. These profiles of DS-5565 are possibly due to its unique binding characteristics to α₂δ-1 and α₂δ-2.