Abstract|Topic: 9 — /INS;Pain| Volume 333, SUPPLEMENT 1, e535, October 15, 2013

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.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect