Novel T-type Calcium Channel Blockers Having Antinociceptive Effect on Inflammatory and Neuropathic Pain Model

초록

A small molecule library of piperazinylalkyl isoxazole and oxazole derivatives was designed, synthesized and evaluated for blocking effects on T-type Ca2+ channel. Several ligands were identified to possess high inhibitory activity for the T-type Ca2+ channel. Among them, the KST005468 was selected for in vivo studies on pain models based on in vitro activity and selectivity over hERG channel binding affinity. The KST005468 showed IC50 value of 1.32 mM ona1G T-type calcium channel that is comparable to mibefradil (0.84 mM). It showed 12 times better activity over hERG channel blocking effect (IC50 = 19 mM). We evaluated the effects of KST5468 through hot plate test, formalin test and two kinds of neuropathic pain models, and KST5468 reduced pain behaviors in those tests. The results of novel synthetic T-type Ca2+ channel antagonist reduced pain-like behaviors in nociceptive, inflammatory and neuropathic pain animal models will be discussed.