Neuropathic pain (Neuralgia)
The sensation of pain is a warning given by the nerves to the brain. For eg: when you put your hand close to a stove, you experience pain indicating you should remove your hand from the stove. But, in patients experiencing neuropathic pain due to nerve damage, they can feel real pain without a cause or do not experience pain when they have to. A sharpshooting, prickling pain characterizes Nerve pain or Neuralgia. One can feel it either only during the middle of the night or all day. It is a type of pain that iother painkillers/ analgesics do not relieve.
Drugs commercially available for managing neuropathic pain
Three Anti-Epileptic drugs that target the calcium channel are available. They are:
- Ziconotide: a snail toxin called conotoxin approved by the US FDA for treating chronic pain
- Gabapentin (GBP) and Pregabalin: target the interaction between CRMP2 and the Calcium channel. Both have low efficacy and serious side effects.
There is an inevitable need to balance pain-relieving effects and minimal side effects.
An important target for painkillers/ analgesics is voltage-gated calcium channels, specifically the Transmembrane Cav2.2 (N-type). By blocking these channels or by indirectly modulating this target, one can reduce chronic pain.
Why is this an important and relevant therapeutic intervention?
Specific sites like the dorsal root ganglia (DRG) or spinal cord dorsal horn (DH) express them. Within the afferent fibers of DH, they release some neurotransmitters. Animal models with neuropathic pain over-express these calcium channels. Blocking the channels reduces the behavioral signs of pain. This is how it became a relevant therapeutic intervention.
CRMP2 and CBD3 for neuropathic pain
A team led by Dr. Rajesh Khanna from the NYU College of Dentistry’s Pain Research Center discovered a potentially promising candidate to treat neuropathic pain.
A molecule called Collapsin Response Mediator Protein 2 (CRMP2) is a regulator of Cav2.2. It targets the calcium channel to the membrane of sensory neurons and enhances the release of neurotransmitters in the DRG thereby regulating their function.
A peptide known as CRMP2-derived peptide (CBD3) uncouples the link between the CRMP2 and Calcium channel. This will prevent the influx of calcium and thereby decrease the release of the transmitter. This will eventually reduce the pain.
Molecular dynamics approach
Much information about the structure of domains responsible for the interaction of Cav2.2 and CRMP2 remains unknown. So, the design of small molecule inhibitors to target this interaction was not possible. This made researchers turn to molecular dynamics for help.
Using a molecular dynamics approach, they were able to identify an A1R2 dipeptide in CBD3 which was necessary to anchor the Cav2.2 motif in the calcium channel. They designed pharmacophore models and screened 27 million compounds using an online ZincPharmer server.
CBD3036 is a potential neuropathic pain reliever
Out of a total of 200 hits, they took 77 candidates for assessment. They studied the influx of calcium because of depolarisation in rat neurons. 9 of them were tested electrophysiologically and 1 (CBD3036) was evaluated biochemically and behaviourally. This CBD3036 could break the connection between CRMP2 and the calcium channel and reduce the calcium channel expression thereby reducing calcium currents. This effect resulted in reduced neurotransmission, reduced calcium response to mechanical stimulation, and reversed pain arising due to neuropathy and inflammation. This was observed in both the genders in the two species and showed no change in sensory, sedative, depressive, and cognitive behaviors. This was the first small molecule inhibitor that achieves analgesia (relieves pain) without any side effects. This suggest CBD3063 as a better analgesic than GBP.
Mechanism of action of CBD3036
Disrupts interaction between calcium channels and CRMP2
Previous results had shown the antagonist action of two peptides related to CBD3 i.e. tat-CBD3 and myr-tat-CBD3. To check if the newly discovered CBD3036 could exhibit a similar potential, they did immunoprecipitation assays and Proximity Ligation Assays (PLA). From the results of both studies, it was confirmed that CDB3036 was able to disrupt the interaction between the calcium channel and CRMP2.
Decreases the Cav2.2 trafficking to the plasma membrane
Immunofluorescence microscopy suggested that Cav2.2 localization was decreased in cells with CDB3036. This way, the Cav2.2 does not reach the sensory neurons
Conclusion
To conclude, CBD3036 is a promising small-molecule inhibitor that relieves neuropathic pain without harmful side effects.
Let me know what’s your take on this promising drug candidate in the comments.
Thanks for sharing!