In a groundbreaking study, a collaborative effort between two institutions has uncovered promising alternative to widely prescribed pain medications – gabapentin and pregabalin.
These drugs, given to nearly 50 million and 10 million Americans respectively in 2020, have been instrumental in managing various conditions, ranging from restless leg syndrome and epilepsy to neuropathy. However, their usage is marred by side effects, with pregabalin even associated with severe consequences, including the potential for fatal outcomes.
Central to the quest for improved pain relief is the exploration of calcium channels, vital in pain signaling through neurotransmitter release. Rajesh Khanna, director of the NYU Pain Research Center, describes glutamate and GABA as the “currency of the pain signal.”
The recently discovered molecule attaches to an internal section of a calcium channel, indirectly controlling its activity. It surpasses gabapentin in efficacy while avoiding undesirable side effects, making it a compelling candidate for pain treatment.
“Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging. Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain,” said Khanna, the senior author of the PNAS study, where his discovery was recorded.
The team focused their efforts on a protein named CRMP2, a key regulator of calcium channels that binds to them internally. A previously discovered peptide derived from CRMP2, constituting a small region of amino acids, capable of disconnecting CRMP2 from the calcium channel.
Upon introducing this peptide, named the calcium channel-binding domain 3 (CBD3) – not to be confused with cannabidiol – to cells, it functioned as a decoy. CBD3 effectively prevented CRMP2 from binding to the internal section of the calcium channel.
Consequently, this interference led to a reduced influx of calcium into the channel, resulting in a decrease in neurotransmitter release. These findings were corroborated in animal studies, demonstrating a consequential reduction in pain.
“At that point, we realized that these two amino acids could be the building blocks for designing a small molecule,” Khanna told NYU press.
Utilizing a computer simulation in collaboration with the University of Pittsburgh, researchers screened a vast library of 27 million compounds to find a small molecule capable of mimicking the inhibitory effects of CBD3.
The stimulation narrowed down the candidates to 77 compounds, with one, named CBD3063, emerging as the most promising.
Khanna’s laboratory conducted tests on CBD3063 using mouse models experiencing pain related to injury. The compound proved effective in relieving pain in both male and female mice. Remarkably, in a direct comparison with the drug gabapentin, the researchers found that significantly lower doses of CBD3063 (1 to 10 mg) were needed compared to gabapentin (30 mg) to achieve pain reduction.
In an effort to investigate the potential of CBD3063 in addressing various forms of chronic pain, Khanna collaborated with researchers from Virginia Commonwealth University, Michigan State University, and Rutgers University. These collaborative studies involved administering CBD3063 to animal models experiencing chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain. Encouragingly, CBD3063 demonstrated success in reversing pain, akin to the affects observed with gabapentin.
Crucially, in contrast to gabapentin, the administration of CBD3063 did not yield any side effects, such as sedation or alternations in cognition, including memory and learning. Additionally, there were no observed changes in heart rate and breathing. This distinguishing feature positions CBD3063 as a promising candidate for pain relief with the potential to outperform existing medications while minimizing adverse effects.
With the promising results from animal studies, the researchers envision the translation of CBD3063 into clinical trials. Their long-term goal is to provide a novel, safe, and effective alternative for pain relief, addressing the limitations and side effects associated with current medications.
“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.
The potential success of CBD3063-derived drugs could revolutionize the field of pain management, offering hope for millions of individuals seeking relief from various chronic conditions.
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