Drugs that can actually help to quit smoking may soon find their way to a pharmacy near you.

Nicotine.

Image credits Lydia / Flickr.

Researchers from the Washington State University (WSU) have synthesized over a dozen compounds that can help smokers curb their dependence on nicotine, a new paper reports. The compounds work by slowing down the rate at which nicotine is broken down in the body, which should help people reduce their consumption of tobacco — or kick the habit altogether.

Breaking down the breaker-downs

Nicotine, like most other drugs, triggers the release of dopamine and serotonin in the brain — two chemicals that make us feel good. However, from the body’s point of view, nicotine isn’t very nice, so it has to go. Our liver produces an enzyme — dubbed CYP2A6 — to break the compound down (or ‘metabolize’ it). This process, however, can have nasty side-effects. Patients who have developed a dependence on nicotine can experience withdrawal symptoms ranging from anxiety and irritability to tingling in their extremities as the substance is flushed out of their system.

The process of metabolization, coupled with our bodies’ tendency to develop tolerance to active substances such as nicotine, means that users tend to increase intake of substances such as nicotine over time.

However, the process of metabolization could also help us kick the habit altogether. In the mid-90s, researchers found that people who had fewer copies of the gene that encodes the CYP2A6 enzyme tend to smoke less and are less likely to become addicted to smoking. In a bid to artificially-induce these traits into people with normal levels of CYP2A6, the team designed dozens of molecules that can bind to the enzyme and limit its ability to process nicotine.

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This is the feeling that the researchers are targeting, said Travis Denton, assistant professor of pharmaceutical sciences, lead author and a former tobacco chewer who has been working on solutions to nicotine dependence for 15 years.

“I quit cold turkey and I know how hard it is. Would this have helped? I believe so, because again, the people who want to quit, really want to quit,” says lead author Travis Denton, assistant professor of pharmaceutical sciences at the WSU.

“They just can’t because it’s too doggone hard. Imagine if you could take this pill and your jitters don’t come on as fast — it’s just super reinforcing to help you quit.”

Co-author Philip Lazarus, Boeing distinguished professor of pharmaceutical sciences, says that inhibiting CYP2A6 shouldn’t have any effect on your overall health.

“If we could specifically target this enzyme, people should be fine, and it will possibly help them stop smoking or at least decrease their amount of smoking.”

So far, the team has been able to test the substances and make sure they don’t interfere with other major enzymes in the body — 18 of their molecules passed the test. The next step is for the Food and Drug Administration to approve clinical trials of the compounds, to see exactly what effect each of these compounds would have on the human body.

Molecules smoking.

Some of the 18 molecules the team developed and tested and their interaction with CYP2A6.
Image credits Travis T. Denton et al., 2018, JoMC.

Should even one of these molecules prove effective, it could bring significant benefits to public health. Smoking is the leading cause of preventable death worldwide, causing an estimated 6 million deaths per year. Cigarette smoking causes nearly one in every five deaths in the United States.

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The paper “Identification of the 4-Position of 3-Alkynyl and 3-Heteroaromatic Substituted Pyridine Methanamines as a Key Modification Site Eliciting Increased Potency and Enhanced Selectivity for Cytochrome P-450 2A6 Inhibition” has been published in the Journal of Medicinal Chemistry.

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