Ziconotide: Neuronal Calcium Channel Blocker for Treating Severe Chronic Pain

Elan Pharmaceuticals, Inc., 7475 Lusk Boulevard, San Diego, CA 92121, USA.
Current Medicinal Chemistry (Impact Factor: 3.85). 01/2005; 11(23):3029-40. DOI: 10.2174/0929867043363884
Source: PubMed


Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

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    • "However, there are examples where the therapeutic potential of a toxin has been realized prior to resolution of the structure of the target ion channel, such as Prialt (ziconotide), a naturally occurring peptide conotoxin from the cone snail Conus magus. The high selectivity of this toxin in blocking N-type calcium channels involved in excitatory neurotransmitter release from primary afferent nerve terminals enabled registration as a drug for treatment of pain (McIntosh et al. 1982; Miljanich 2004). Another heralded achievement was the engineering of ShK 192, a highly active analogue of the naturally occurring toxin peptide ShK-L5 from the sea anemone Stichodactyla helianthus, to blocking of K v 1.3 channels and raising a therapeutic potential in autoimmune diseases mediated by effector memory T cells (Pennington et al. 2009). "
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    • "conotoxins) or, in general, disrupting critical biochemical signalling networks within the prey's body [61], low doses of these peptides can actually counteract disturbances from diverse disorders. Accordingly, toxic peptides may aid in treating pain [41], neurological and cardiovascular diseases, diabetes and cancer [32]. A prominent example is the type 2 diabetes drug Exenatide, a synthetic version of a glucagon-like peptide-1 analogue found in the venom of the Gila monster Heloderma suspectum [7]. "
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    • "Increasing the rate of species description for conoideans is crucial for two main reasons: (1) Their potential susceptibility to environmental threats, as many of them are members of coral reef communities; and (2) conoidean venoms are rich in neuropeptides that are important tools for biochemical investigations of neuronal signaling and have relevant pharmacological applications. Conoidea is one of the most promising animal groups for the discovery of novel pharmacologically active neuropeptides, as exemplified by the development of the first drug from a cone snail conopeptide, ziconotide (Prialt), which is used to alleviate chronic pain in HIV and cancer patients [28]. Traditional taxonomic approaches, based mainly on shell characters, are of little value to identify conoidean species [29], [30], and recent DNA-based taxonomic studies demonstrated that the traditional taxonomic framework of conoideans is largely inadequate [27], [31]–[33]. "
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