NYU scientists discover promising new candidate for pain treatment

Predicting analgesic compounds based on a two amino acids peptide to treat chronic pain.

A new compound reversed four types of chronic pain in animal studies, according to research led by New York University (NYU) College of Dentistry’s Pain Research Center.

The small molecule, 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 signalling, in part through the release of neurotransmitters such as glutamate and GABA.

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.

“Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging,” said Rajesh Khanna, Director of the NYU Pain Research Center and Professor of molecular pathobiology at NYU Dentistry. “Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain.”

A first-in-class small molecule

Protein CRMP2 is a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. Khanna and his colleagues discovered a peptide (CBD3) derived from CRMP2 that could uncouple CRMP2 from the calcium channel.

In collaboration with the University of Pittsburgh, the researchers ran a computer simulation that screened a library of 27 million compounds to look for a small molecule that would “match” the CBD3 amino acids.

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.

Long-term, the scientists hope to bring a CBD3063-derived drug to clinical trials to offer new options for safe and effective pain relief.

“Identifying this first-in-class small molecule has been the culmination of more than 15 years of research. Though our research journey continues, we aspire to present a superior successor to gabapentin for the effective management of chronic pain,” said Khanna.

Image: Predicting analgesic compounds based on a two amino acids peptide to treat chronic pain. Credit: Drs Ulises Santiago and Samantha Perez-Miller.

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