In a groundbreaking effort, a collaborative team spanning two institutions meticulously examined a vast library of 27 million diverse molecules, uncovering some that exhibit superior efficacy compared to the currently prescribed pain medications, gabapentin and pregabalin.
Gabapentin, administered to nearly 50 million Americans in 2020, serves as a remedy for a spectrum of conditions such as pain associated with restless leg syndrome, epilepsy, hot flashes, and neuropathy. On the other hand, pregabalin, prescribed to nearly 10 million Americans, carries the burden of more severe side effects, some of which may even lead to fatal consequences.
The intricate web of pain signaling revolves around calcium channels, pivotal players in the process. These channels influence pain communication by releasing neurotransmitters like glutamate and GABA, which Rajesh Khanna, the director of the NYU Pain Research Center, aptly refers to as “the currency of the pain signal.”
The breakthrough came in the form of a newly identified molecule that selectively binds to an inner region of a calcium channel, indirectly modulating its activity. Impressively, this molecule outperforms gabapentin in terms of efficacy, while avoiding the troublesome side effects associated with the current medications. This discovery marks a significant stride toward developing a promising candidate for pain treatment, holding the potential to revolutionize the landscape of pain management.
“Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging,” said Khanna. He is the senior author of the PNAS study that recorded his discovery. “Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain.”
The focal point of this study revolved around CRMP2, a pivotal regulator of the calcium channel that binds to it internally. Earlier investigations by the researcher and colleagues led to the identification of a peptide derived from CRMP2, designated as the calcium channel‐binding domain 3, or CBD3 (distinct from cannabidiol). This peptide demonstrated the ability to disengage CRMP2 from the calcium channel.
Upon introducing CBD3 to cells, it functioned as a decoy, preventing CRMP2 from binding to the interior of the calcium channel. The consequence of this interference was a reduction in calcium influx through the channel and subsequently decreased neurotransmitter release. In animal studies, this translated to a tangible reduction in pain.
Peptides pose challenges as drug candidates due to their short duration of action and susceptibility to degradation in the stomach. To overcome these limitations, the researchers aimed to develop a small molecule drug based on CBD3. They commenced with the 15 amino acids constituting the CBD3 peptide, focusing on two specific amino acids identified in previous studies as responsible for inhibiting calcium influx and alleviating pain.
“At that point, we realized that these two amino acids could be the building blocks for designing a small molecule,” Khanna said when he spoke to the NYU press.
In partnership with colleagues from the University of Pittsburgh, researchers conducted a computer simulation aiming to identify a small molecule within a library of 27 million compounds that could effectively interact with CBD3 amino acids. The simulation efficiently narrowed down the selection to 77 compounds, all of which were subjected to experimental testing to assess their ability to reduce calcium influx. Among these, CBD3063 emerged as the most promising candidate for pain treatment.
Further investigations in Khanna’s lab involved testing CBD3063 on mouse models experiencing pain due to injury. The compound demonstrated effectiveness in alleviating pain in both male and female mice. Notably, in a comparative analysis with the drug gabapentin, significantly lower amounts of CBD3063 (1 to 10 mg) were required to achieve pain reduction compared to gabapentin (30 mg).
To explore the potential applications of CBD3063 in various types of chronic pain, Khanna collaborated with researchers from Virginia Commonwealth University, Michigan State University, and Rutgers University. Their joint studies involved administering CBD3063 to animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain—all of which showed successful reversal of pain, similar to the effects of gabapentin.
Crucially, unlike gabapentin, the use of CBD3063 did not induce side effects such as sedation, cognitive changes (including memory and learning), or alterations in heart rate and breathing.
The researchers aspire to progress toward clinical trials with a drug derived from CBD3063, aiming to provide novel options for safe and effective pain relief in the future.
“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,” Khanna shared.
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