After screening 27 million compounds, researchers have found a small-molecule drug that performed as well as a common painkiller with no side effects in rodent tests. The hope is that the finding could lead to better pain management for humans.

The focus of the research, led by scientists at NYU College of Dentistry’s Pain Research Center, was to look at the regulation of calcium channels. These pathways in the body are a critical part of the way in which pain is communicated. When stimulated, they release neurotransmitters including glutamate and GABA, which is “the currency of the pain signal,” according to Rajesh Khanna, senior author of the study. Khanna has previously developed a gene-therapy targeting sodium channels, another of the body’s pain signaling mechanisms, to reverse chronic pain.

Some current pain-relieving drugs such as gabapentin and Lyrica act by binding to the outside of calcium channels known as Cav2.2 to regulate its activity, but they often carry serious side effects along with them including dizziness, trouble breathing, unsteadiness, dementia, delusions, and more.

Inside track

The new research focused on a peptide (a small chain of amino acids) called CBD3, previously discovered by Khanna and his colleagues, that works on the inside of the calcium channel instead.

When introduced to cells, CBD3 stopped a protein called CRMP2 from binding to the inside of the calcium channel. This led to less calcium gathering in the channel which, in turn, dampened the release of neurotransmitters and, subsequently, reduced pain.

The problem is that peptides like CBD3 are hard to synthesize as drugs and they are fairly fragile, breaking down inside the stomach. So the team set out to find a small molecule drug that would work like CBD3. After running computer simulations that examined 27 million compounds, the researchers found one that they felt would do the trick: CBD3063.

“Many scientists have screened the same library of compounds, but have been trying to block the calcium channel from the outside,” said Khanna. “Our target … is on the inside of the cell, and this indirect approach may be the key to our success.”

Four types of pain

Next, the team tried out the compound in four different mouse models of pain: injury induced; inflammatory; chemotherapy-induced; and trigeminal nerve pain, which is a type of chronic pain affecting the face. To see if CBD3036 had any effect in mitigating the pain, the researchers used a variety of techniques.

For mechanical pain, the paws of the mice were touched by hair-like filaments of increasing force. “A mouse with no pain will not remove its paw even to the highest force filament whereas a mouse in pain will withdraw its paw even to the smallest force filament applied,” Khanna told New Atlas. A cold aversion test was also used by applying acetone to the paws of the mice, which creates a cooling sensation. If the mice reacted quickly, Khanna says, that indicates a higher degree of pain.

In all cases, the CBD3036 significantly reduced the pain experienced by the mice and had no reported side effects. Plus, with regard to the injury-related pain, only 1-10 mg of the compound was needed to lower pain levels versus 30 mg of gabapentin.

The researchers are now investigating the safety of CBD3036 more thoroughly and looking to see if tolerance develops during extended use. They hope to eventually move to clinical trials.

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

The research will be published in the journal PNAS later this week.

Source: New York University