N-type calcium channel blockers in pain and stroke

N-type calcium channels are located at presynaptic termini throughout the central nervous system (CNS), where they play a key role in the regulation of neurotransmitter release. In the pain pathway, N-type calcium channels in the spinal cord directly mediate spinal transmission of pain signals from the periphery to the CNS. In cerebral ischaemia, neuronal injury is also, in part, mediated through the activity of IV-type calcium channels. The recent development of a selective IV-type calcium channel blocking peptide, SNX-111 (Ziconotide, Neurex Corp., USA) has shown unequivocally that the N-type calcium channel is an important drug target for both analgesia and neuroprotection. SNX-111 is now in late stage clinical development for the treatment of various acute and chronic pain states, brain damage following cerebral ischaemia, closed head trauma and coronary artery bypass surgery. Over the last decade, the search for a selective small molecule blocker of N-type channels has been intense and has resulted in the discovery of a number of promising compounds, although none so far have been reported to have entered clinical trials.