Bioorganic & medicinal chemistry
-
Neuropathic pain is a serious physical disabling condition resulting from lesion or dysfunction of the peripheral sensory nervous system. Despite the fact that the mechanisms underlying neuropathic pain are poorly understood, the involvement of voltage-gated calcium (Ca(V)) channels in its pathophysiology has justified the use of drugs that bind the Ca(V) channel α₂δ auxiliary subunit, such as gabapentin (GBP), to attain analgesic and anti-allodynic effects in models involving neuronal sensitization and nerve injury. GBP binding to α₂δ inhibits nerve injury-induced trafficking of the α₁ pore forming subunits of Ca(V) channels, particularly of the N-type, from the cytoplasm to the plasma membrane of pre-synaptic terminals in dorsal root ganglion neurons and dorsal horn spinal neurons. ⋯ In addition, using the patch clamp technique we show that GZ4 treatment significantly decreased whole-cell currents through N-type Ca(V) channels heterologously expressed in HEK-293 cells. Interestingly, the behavioral and electrophysiological time course of GZ4 actions reflects that its mechanism of action is similar but not identical to that of GBP. While GBP actions require at least 24 h and imply uptake of the drug, which suggests that the drug acts mainly intracellularly affecting channels trafficking to the plasma membrane, the faster time course (1-3 h) of GZ4 effects suggests also a direct inhibition of Ca(2+) currents acting on cell surface channels.