Looking where others have not

For decades, scientists have searched for a synthetic alternative to medical marijuana that can deliver its medicinal benefits without the harmful side effects. The problem is that the positives and negatives are tied together at the molecular level, and no one has found a way to separate them.

Like a determined prospector, pharmacy professor Ganesh Thakur found a promising new vein by looking where others have not. His recent patent, which won an “Invented Here!” award from the Boston Patent Law Association in November, has the potential to produce a mother lode of new medications to treat addiction related to alcohol, tobacco, marijuana, hallucinogens, and opioids.

While his work is still in the pre-clinical stage, animal testing indicates that his approach could give pharmacologists precision controls of the brain’s cannabinoid receptors, which are the proteins affected by marijuana.

Need for precision

Scientists have known for decades that THC, the active ingredient in marijuana, affects the brain by attaching to the CB1 cannabinoid receptors. They also know that the CB1 receptors control naturally occurring chemicals, similar to THC, that regulate mood, pain, appetite, memory, and more.

The strategy to date has been to develop synthetic compounds that can either reduce or enhance the sensitivity of the CB1 receptor by adjusting its ability to send signals to the brain. The problem is that either one of these actions affects a whole range of brain activities.

“This receptor is a very important molecular target for treating diseases, but you have to be very careful when you turn down the signaling because you can cure one problem and create another,” said Thakur. “When you turn it down, you reduce addiction, but you may also elevate depression.”

In 2006, the pharmaceutical industry thought it that had its first big CB1 breakthrough with the release of Rimonabant in Europe to treat obesity. The drug worked by blocking CB1 signaling, which did a superb job of decreasing appetite, but it also diminished the patient’s sense of well-being.

The drug was pulled from the market worldwide in 2008 after studies showed a significant increase in depression and suicidal thoughts among users.

“Rimonabant was taken off the market and several related discovery projects were shut down across the United States because the CB1 receptor was perceived to be such a risky target,” said Thakur. “That was a big blow to the pharmaceutical industry and cannabinoid researchers.”

Looking elsewhere

It was about this same time that Thakur began taking a different approach. Rather than targeting the primary (orthostatic) site on the CB1 receptor, which is extremely imprecise, he began to look at an adjacent (allosteric) part of the CB1 protein. Using the allosteric site, he believed he could develop molecules that provided more precise controls that would allow scientists to control one function of the CB1 at a time. This is important because it would allow drug-makers to avoid unwanted side effects, such as the high from marijuana or the depression caused by Rimonabant.

If this strategy is successful, it could lead to an entirely new class of drugs for a large range of ailments including neuropathic pain, PTSD, eating disorders, epilepsy, Alzheimer’s, glaucoma, and drug abuse.

The key to this line of research lies in PAMs and NAMs—positive or negative allosteric modulators—which either dial up or dial down the receptivity of a particular element of the CB1 receptor.

As Thakur sees it, Holy Grail is a medication for human use that will control addiction without inhibiting a person’s natural ability to experience happiness.

“This is where the gem of this discovery lies,” said Thakur. “There are millions of Americans currently addicted to opioids.”

The rate of opioid overdose deaths in the U.S. is a staggering 134 a day, according to the National Institutes of Health, while opioid abuse is estimated at 11 million Americans.

Thakur has already demonstrated that his methodology and compounds can control alcohol addiction in laboratory animals, which is the basis for his patent. He believes this success bodes well for similar results with opioids, nicotine, methamphetamines, and the synthetic marijuana known as Spice.

But translating success at the pre-clinical stage into medications approved for humans will take several years and millions of dollars. To do this, the Thakur Lab at Northeastern is working with collaborators in four countries and seven states, as well as the National Institutes of Health.

“Ultimately, this is going to take cooperation between academia and industry,” he said. “Industry has the money and resources needed for expensive clinical trials on humans, and academia can take the more innovative approaches needed to develop safer and more effective medications.”


Photo credit: Matt Modoono 

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