New Compound Outperforms Pain Drug by Indirectly Targeting Calcium Channels

A compound which binds to an inner region of a calcium channel to indirectly regulate it, outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain.

Calcium channels play a central role in pain signaling, in part through the release of neurotransmitters such as glutamate and GABA according to Rajesh Khanna, director of the NYU Pain Research Center. The Cav2.2 (or N-type) calcium channel is the target for three clinically available drugs, including gabapentin (sold under brand names including Neurontin) and pregabalin (Lyrica), which are widely used to treat nerve pain and epilepsy.

Gabapentin mitigates pain by binding to the outside of the Cav2.2 calcium channel, affecting the channel’s activity. However, like many pain medications, gabapentin use often comes with side effects.

Khanna has long been interested in a protein called CRMP2, a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. He and his colleagues previously discovered a peptide (a small region of amino acids) derived from CRMP2 that could uncouple CRMP2 from the calcium channel. When this peptide — dubbed the calcium channel-binding domain 3, or CBD3 — was delivered to cells, it acted as a decoy, blocking CRMP2 from binding to the inside of the calcium channel. This resulted in less calcium entering the calcium channel and less neurotransmitter release, which translated to less pain in animal studies.

Peptides are difficult to synthesize as drugs because they are short-acting and easily degrade in the stomach, so the researchers sought to create a small molecule drug based on CBD3. Starting with the 15 amino acids that make up the CBD3 peptide, they honed in on two amino acids that studies showed were responsible for inhibiting calcium influx and mitigating pain.

“At that point, we realized that these two amino acids could be the building blocks for designing a small molecule,” said Khanna.

One compound, which the researchers named CBD3063, emerged as the most promising candidate for treating pain. Biochemical tests revealed that CBD3063 disrupted the interaction between the CaV2.2 calcium channel and CRMP2 protein, reduced calcium entering the channel, and lessened the release of neurotransmitters.

Khanna’s lab then tested CBD3063 with mouse models for pain related to injury. The compound was effective in alleviating pain in both male and female mice — and notably, in a head-to-head test with the drug gabapentin, the researchers needed to use far less CBD3063 (1 to 10 mg) than gabapentin (30 mg) to reduce pain.

To explore whether CBD3063 helped with different types of chronic pain, Khanna partnered with other researchers and ran similar studies administering CBD3063 to treat animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain — all successfully reversing pain, similar to gabapentin.

But unlike gabapentin, the use of CBD3063 did not come with side effects, including sedation, changes to cognition such as memory and learning, or changes to heart rate and breathing.

The researchers are continuing to study CBD3063, refining its chemical composition and running additional tests to study the compound’s safety and assess if tolerance develops.

Sources:

Kimberly Gomez, Ulises Santiago, Tyler S. Nelson, Heather N. Allen, Aida Calderon-Rivera, Sara Hestehave, Erick J. Rodríguez Palma, Yuan Zhou, Paz Duran, Santiago Loya-Lopez, Elaine Zhu, Upasana Kumar, Rory Shields, Eda Koseli, Bryan McKiver, Denise Giuvelis, Wanhong Zuo, Kufreobong E. Inyang, Angie Dorame, Aude Chefdeville, Dongzhi Ran, Samantha Perez-Miller, Yi Lu, Xia Liu, Handoko, Paramjit S. Arora, Marcel Patek, Aubin Moutal, May Khanna, Huijuan Hu, Geoffroy Laumet, Tamara King, Jing Wang, M. Imad Damaj, Olga A. Korczeniewska, Carlos J. Camacho, Rajesh Khanna. A peptidomimetic modulator of the Ca V 2.2 N-type calcium channel for chronic pain. Proceedings of the National Academy of Sciences, 2023; 120 (47) DOI: 10.1073/pnas.2305215120

Materials provided by New York University. Note: Content may be edited for style and length.

New York University. “New compound outperforms pain drug by indirectly targeting calcium channels.” ScienceDaily. ScienceDaily, 13 November 2023. <www.sciencedaily.com/releases/2023/11/231113155221.htm>.

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