N-Type Calcium Channel Blockers

A structurally diverse array of N-type calcium channel antagonists has been reported, and two recent extensive reviews have summarized the structures and associated data through 2008 [59,60]. Among these 

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The benzhydryl substituent is common to many reported N-type calcium channel blockers. A recently reported series derived from the neuroepileptic flunarizine (5), which exhibits N-type calcium channel potency in a whole-cell patch-clamp assay (IC50 0.08 iM) as well as L-type potency... 

Atanassoff, P.G., Hartmannsgruber, M.W.B., Thrasher, J., Wermeling, D., Longton, W., Gaeta, R., Singh, T., Mayo, M., McGuire, D., Luther, R.R. Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain, Reg. Anesth. Pain Med. 2000, 25, 274-278. 

Cox, B., Denyer, J.C. N-type calcium channel blockers in pain and stroke, Exp. Opin. Ther. Patents 1998, 8, 1237-1250. 

Malmberg, A.B. and Yaksh, T.L. Effect of continuous intrathecal infusion of co-conopeptides, N-type calcium-channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats, Pain 1995, 60, 83-90. 

Conotoxin MVIIA, an N-type calcium channel blocker Conus magus... 

Besides their therapeutic applications, conotoxins have exhibited great potential for the development of neurological probes. Conotoxins are currently being used in hundreds of research laboratories for a wide variety of physiological investigations. Some conotoxins have become well-established neurobiological tools. They can also be used as antagonists of specific subtypes in functional studies for example, w-conotoxin MVIIA is used as a specific N-type calcium channel blocker. Conotoxins are also utilized in research to provide information on the role and distribution of different receptor subtypes. Undoubtedly, these research applications will continue to expand. 

Smith MT, Cabot PJ, Ross FB, Robertson AD, Lewis RJ. The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain 2002 96(l-2) 119-27. 

Figure 14.26 Ziconotide N-type calcium channel blocker (Prialt ).

Kim, J. L, Takahashi, M., Ohtake, A., Wakamiya, A. and Sato, K. 1995. Tyr is essential for the activity of co-conotoxin MVIIA and GVIA, specific N-type calcium channel blockers. Biochem. Biophys. Res. Comm. 206 449-454. 

Cypros Pharm. Corp. describes the use of polyguanidino derivatives as presynaptic N- and P/Q-type calcium channel blockers for i.v. (or i.c.v.) administration (Marangos et al. (Cypros Pharmaceutical Corp.), W09836743). Compound 5 was administered to gerbils (7.5 mg/kg i.v.) prior to bilateral carotid occlusion. After 72 h the animals were sacrificed. Brains were perfusion-fixed and sections were stained to enable quantitative cell counts of live and dead neurons. The number of damaged neurons in the subiculum was 91.5 compared to 214 for a control treated with saline. It has been claimed that this compound can be used for the treatment of neuropathic pain and for the protection of neurons from excitatory damage under conditions of cerebral hypoxia. 

Nishiya Y, Kosaka N, Uchii M, Sugimoto S. 2002. A potent 1,4-dihydropyridine L-type calcium channel blocker, benidipine, promotes osteoblast differentiation. Calcif Tissue Int 70 30-9. 

Aga IVA and ro-conotoxin GVIA are standard tools in elucidating the roles of P/Q-type and N-type calcium channels in synaptic transmission. In many types of synapses, application of either toxin may mediate moderate inhibition of neurotransmitter release, whereas co-application of both blockers may almost abolish synaptic transmission due to the nonlinear dependence of synaptic release on intracellular calcium concentration. On a final note, we should add that there are many other species of cone snails and spiders that produce active toxins which selectivity inhibit specific calcium channel subtypes (for example, co-conotoxins GVIB, GVIC, GVIIA, SVIA, SVIB), and it is likely that many more remain to be discovered (Olivera et al. 1994). 

NMR Structure of Ziconotide A Novel Treatment for Pain. MVIIA, now known as Ziconotide, is a 25-amino acid peptide originally discovered from the venom of the marine cone snail. Conus magus. Like other to-conotoxins it is a potent blocker of N-type calcium channels, giving it a wide range of potential therapeutic applications. When delivered intrathecally (i.e., through spinal infu-... 

Bowersox, S.S., Gadbois, Th., Singh, T., Pettus, M., Wang, Y.-X., Luther, R.R. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX - 111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain, J. Pharmacol. Exper. Ther. 1996, 279, 1243-1249. 

Brose, W.G., Gutlove, D.P., Luther, R.R., Bowersox, S.S., McGuire, D. Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain, Clin. J. Pain, 1997, 13, 256-259. 

Zemzemi N, Rodriguez B (2015) Effects of L-type calcium channel and human ether-a-go-go related gene blockers on the electrical activity of the human heart a simulation study. Europace... 

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