Analgesic actions of the N-type voltage-dependent calcium channel blockers

OBJECTIVE The participation of N-type voltage-dependence calcium channel(N-VDCC) in pain transmission has been proved,and the analgesia of N-VDCC blokcers has also been confirmed.The aim of this study was to obtain the small molecular N-VDCC blockers with oral analgesic activity and tho investigate the characteristics of its analgesia.METHODS Taken NMED-160 and ZC88 as leading compounds,a series of candidates of non-peptide N-VDCC blockers were synthesized.The inhibition of these chemicals to N-VDCC currents was tseted by using two-electrode voltage-clamp technique,and the oral analgesic activity was detected by using the model of chronic construction injury of sciatic nerve(CCI) in rats,a classic model of neuropathic pain.Among these compounds,D304 was selected to further investigate its analgesic action by using a variety of acute and chronic pain models.RESULTS Among these compounds we synthesized,eight compounds displayed high activity of inhibiting N-VDCC currents,and D214 and D304,showed strong oral analgesic activity in the rat CCI model.According to these results,D304 was selected to further study its analgesic action.In the mouse 55℃ hot-plate model,D304 given by oral route(10,30,100 mg·kg-1) failed to observed significant analgesia,suggesting that D304 had no effect on the thermal-stimulated acute pain.In the rat formalin-induced persistent pain model,D304 administered orally(10,30,100 mg·kg-1) dose-dependently inhibited formalin-induced pain in phaseⅡ,rather than in phaseⅠ,with equivalent intensity of analgesia to positive control of NMED-160.In the rat complete Freund adjuvant-induced chronic inflammatory pain model,D304(10,30,100 mg·kg-1,po) dose-dependently inhibited mechanical-stimulated allodynia and thermal-stimulated hyperalgesia,and its analgesic strength was equal to or even slightly stronger than that of NMED-160.In the two classical peripheral neuropathic pain models-the rat CCI model and the rat diabetic peripheral neuropathic pain model,D304(10,30,100 mg·kg-1,po) dose-dependently inhibited mechanical-stimulated allodynia and thermal-stimulated hyperalgesia,and its analgesic strength was slightly stronger than that of NMED-160 or gabapentin.The preliminary safety evaluation showed that the LD50 of D304(po) was 570 mg·kg-1,and therapeutic index was about 10.CONCLUSIONTaken together,we designed and synthesized a series of samll molecular N-VDCC blockers with oral analgesic activity.Among these compounds,D304 had no significant analgesia to acute pain,but showed strong oral analgesic activity to persistent and chronic pain,especially to chronic inflammatory pain and neuropathic pain.This findings set up a foundation for the further research and development of samll molecular N-VDCC blockers with oral analgesic activity.