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A dysregulation in function of neuronal low-voltage-activated T-channel causes neuropathic pain. A group of ten 1,4-disubstituted and 1,4,4-trisubstituted piperidines were synthesized through short sequences of reactions from 4-cyanopiperidine, which may potentially produce a library of analogs. Inhibitions of T-channel in rat dorsal root ganglion neurons and/or Cav3.2 channel in human embryonic kidney-293 cells were screened, and subsequent analgesic effects and inhibition of seizure in pentylenetetrazole-induced seizure mouse model were examined. The two most promising piperidine molecules showed analgesic effects in rat model using a spared nerve injury protocol. One displayed a long withdrawal latency in response to thermal stimulation, and an 80% increase in mechanical threshold assessment studies.

Synthesis of 1,4- and 1,4,4-substituted piperidines for the inhibition of neuronal T-type Ca2+ channels and mitigation of neuropathic pain in mice