Ready or ready, here they come! The new oral N type calcium channel blockers. Merck appears to be the flagbearer and we can only hope they have fierce competitors nipping at their heels. This venture represents a brave step for Merck after their recent pounding over Vioxx. We are so grateful they have not given up on pain research. Go Merck!
We have previously written on the entry of Merck into pain research. They have formed an agreement with Neuromed Pharmaceutical to market NMED-160, which is an ORAL N-type calcium channel blocker. As a prior article here discusses, N-type calcium channels are the ones found in NEURONS. CaV2.2 is the N-type associated with PAIN neurons. This is the beginning of a new era in pain medicines. Merck predicts strength on the level of morphine. We will present more on this as soon as possible.
Passing on another topic of interest, the recent discovery of T type (transient type) calcium channels which are thought to be related to gene activated cell replication and growth in injury, we are thrilled to note the expanding knowledge about N type channels. We are aware that neuronal P/Q type channels have been recently discovered in small arteries, in research on the heart. There, cilnidipine (see below), an L and N type blocker, was found to treat heart dysfunction secondary to high blood pressure. The evidence points surprisingly to the beneficial effect of cilnidipine in limiting growth factors which act on the heart. If you have been paying attention, (see recent article on BDNF) gene overproduction of nerve growth factors is thought to drive the maintenance of hypersensitization in nerve injury pain. Still, it is the the N type calcium channel where the action currently is in pain, not the P/Q.
Research on N type calcium 2+ channel blockers, specifically the voltage gated CaV2.2 channel, has been moving along with surprising rapidity. Everything associated with pain seems to move at a snail’s pace, but that would be true in severe CP, even if they could come up with a cure in one day.
The chinese bird spider has been found to have venom which blocks N type channels. The N type channel isoforms include GVIA (the most studied and the first target for pain, and the active site for ziconotide), HTWX-X, and MVIIA. The HTWX-X stands for the huwentoxin-X N type isoform, and huwentoxin is a neurotoxin found in the chinese bird spider. Surprisingly, huwentoxin is also active against GVIA. This neurotoxin is a relatively small peptide with only 28 amino acids in the sequence, six of which are cystine. Inhibition is by way of a “cystine knot”. The block is reversible, making the toxin an interesting target for study. Presumably any pain medicine derived would be administered parenterally (SubQ, IM or IV) or intrathecally.
(See the report by Liu et al J Biol Chem Jan 26 2006).
Theoretically, any broad calcium channel blocker should stop pain, but what else does it stop? The N type channel blocker seems uniquely able to stop pain without hurting other functions. As Yamamoto et al point out in Bioorg Med Chem Let Feb 2006, the problem with using L type blockers is that L type channels are needed for the heart to beat. These researchers took cilnidipine and found a derivative of it, named N type channel blocker 21b, which DOES cause analgesia but has 1600 fold less activity against L type channels than cilnidipine. Variants on this molecule might be breakthrough medicines, stopping pain without stopping the heart.
The N type channel receptors exist in several isoforms. Page et al in Nov 2005 Neuroscience report that GABA(B) receptors are now thought to decrease flow through N type channels via a G protein. G proteins are necessary facilitators of other reactions and may be carriers, connectors etc. GABA(B) was studied in the vagus nerve, one of the cranial nerves which travels down through the body to gut and other viscera. The vagus is not only supply but also an afferent (return route) for sensation. Baclofen is a noted GABA(B) agonist, or promoter (ie. the opposite of antagonist). The bowel, bladder, and gut have a lining or mucosa which is very sensitive to mechanical stretch and/or tension, which causes pain (think of gas distention). BOTH Baclofen AND omega conotoxin (ziconotide, which blocks the GVIA isoform of N channels) blocked the vagal mechanical receptor in the gut mucosa. What was surprising was that both these agents, baclofen and conotoxin were found to be affecting not only the N type calcium channel receptors but also the inward rectifying potassium channels, which are linked to the presence of acid around the cell membrane. It may be possible to use both an N type channel blocker as well as one which inactivates the inward potassium channel to potentiate relief of central pain in the gut and bladder.
As if all this linkup were not interesting enough, Petzold et al in Nov Brain Research 2005 found that our old friend, nitric oxide (NO was originally of interest only in the development of Viagra) modulates calcium entry via not only the P/Q Calcium receptors but ALSO the NMDA receptors. Numerous reports of headache from Viagra have been received in those with Central Pain in the trigeminal system (facial central pain). These authors found an association with potassium induced Ca2+ increase was amplified by blocking the formation of nitric oxide and diminished by enhancing the formation of NO. This suggests that CP headache might involve actions of NO other than potassium induced Ca2+ increase.
Wada et al in Neurochem Res Aug 2005 found that cells genetically competent to manufacture the Cav2.2 channel subunit alpha1b, could be inhibited by calmodulin, but were not inhibited by a blocker of the MVII isoform of N channels.
Finally, we cite Chen et al J Neurosci Oct 15 2005, who studied the RGK group of small proteins which bind guanosine triphosphate (GTP), which is similar to ATP (see elsewhere at this site) an energy providing molecule. They found that one member of the RGK proteins (which are themselves associated with the Ras group-see elsewhere at this site), known as Rem2 interferes not only with the assembly of N type calcium channels but also interferes with calcium trafficking by the channels which do form. Even more oddly, omega conotoxin bound equally well to the channels, even when Rem2 had totally abolished calcium flow through the channels, suggesting different mechanisms for ziconotide and Rem2. This indicates that even MORE possibilities exist for developing therapeutic agents against N type calcium channels.
In the meantime, the announcement by Merck that they plan to spend about 40 million dollars to study NMED-160 and up to 400 million to promote it if it passes trials is a sure indication that the big drug companies are finally seriously addressing the need for pain medicines other than opiates. Since many of these are thought to benefit neuropathic pain, those of us with central pain can hardly contain ourselves, as we hope for the realization of the first, but certainly not the last, ORAL medicine which actually treats central pain.