Advances in the development of Cav2.2 (N-type) calcium channel blockers as analgesics.
SummaryAccording to LeadDiscovery's recent feature report, Pain Therapeutics 2005, about one and a half billion people suffer from moderate to severe chronic pain worldwide, driving the market for analgesics to nearly $23 billion in 2004. Many companies are investing heavily in the development of new pain therapeutics, even more so now with the recent problems to have hit the Cox-II inhibitors. Calcium channel blockers stepped into the spotlight at the end of last year with the FDA approval of Elan's Z
According to LeadDiscovery's recent feature report, Pain Therapeutics 2005, about one and a half billion people suffer from moderate to severe chronic pain worldwide. The value of the pharmaceutical market for pain relief reflects this seeming worldwide epidemic of pain, with the overall value reaching nearly $23 billion in 2004. The Cox-II inhibitors, once a thriving class of analgesic agents, have suffered well documented problems over the past year leaving much of the burden of responsibility, at least in the short term, on opioids, triptans, anticonvulsants and traditional NSAIDs. The dynamics of this market have been altered greatly as a result of COX-II-related problems and companies are attempting to fill the void with a new wave of therapeutic classes such as the vanilloids and cannabinoids. Another area that is being extensively mined for new molecular targets includes the voltage-activated Ca channels. Ca channel blockers stepped into the spotlight at the end of last year with the FDA approval of Elan's Ziconotide (PRIALT), an intrathecally administered peptide that blocks the Cav2.2 (N-type) channel. Here we focus on new research describing a constituent of the venom from the Brazilian Wandering Spider as another Cav2.2 channel blocker.
Voltage-activated Ca channels play a major role in many physiological processes including release of neurotransmitters and the regulation of neuronal excitability. Furthermore, dysfunction of Ca channels is implicated in numerous CNS disorders ranging from epilepsy to chronic pain. Considerable efforts have focused on the identification of Ca channels modulators to facilitate functional characterization; screening efforts and; medicinal chemisty. The naturally occurring ù-conotoxins have activity at various Ca channels including the N- (Cav2.2), P/Q- (Cav2.1), R- (Cav2.3), and T- (Cav3.1/3.2) type channels and have served as platforms for the development of therapeutic agents now in development.
The JPET paper highlighted here reports the activity of PnTx3-6, a peptide isolated from the toxin of the P. nigriventer spider and which has little structural similarity with other peptidic toxins. The authors of this paper studied the effect of PnTx3-6 on a panel of recombinant Ca channels and on Ca channel currents recorded from neuroblastoma cells. Electrophysiological data demonstrated that like ù-conotoxins, PnTx3-6 blocks the conductance of Cav2 family members. Cav2.2 (N-type) channels were most sensitive to PnTx3-6, blocked at low nanomolar potency, with activity observed in both transfected HEK cells and neuroblastoma cell lines.
Blockade of Cav2.2 (N-type) channels has previously been shown to prevent pain transmission and activity against this channel has been proposed as the mechanism of action of Ziconotide, a neuroactive peptide developed by Elan as a novel non-opioid treatment for severe chronic pain. Ziconotide is the synthetic equivalent of another naturally occurring toxin (the venom of the marine snail, Conus magus). This mechanism of action distinguishes Ziconotide from all other available 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. In clinical studies, 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. The success of Ziconotide has validated the neuroactive venom peptides as a source of new and useful medicines.
Elan announced FDA approval of Ziconotide for the management of severe chronic pain in December 2004. Since Ziconotide is administered intrathecally, its approval was limited to patients who are intolerant of or refractory to other treatments. FDA approval of Ziconotide was based on the treatment of more than 1,200 patients and three Phase III clinical trials. The most recent Phase III trial conducted at 39 sites in the US and studying 220 adults with opioid-resistant, severe chronic pain demonstrated that the Visual Analog Scale of Pain Intensity (VASPI) score was improved by Ziconotide (press release).
The present study of PnTX3-6 may prompt its further evaluation of as a clinical candidate. However a more attractive outcome of the PnTX3-6 study highlighted here may be the development of small molecule mimics of this peptide. Using the structure of PnTX3-6 as a starting point to identify novel pharmacophores for N-type calcium channel blockers or as a template for the design of small molecule mimics may allow the development of agents with similar efficacy to that of Ziconotide but which are suitable for systemic or even oral administration.
Source: LeadDiscovery's TherapeuticAdvances - original article J Pharmacol Exp Ther. 2005 Jun 2; [Epub ahead of print] featured in DailyUpdates-CNS Diseases