Public Release: 

Addictive nut's derivatives could help smokers break the nicotine habit

American Chemical Society

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IMAGE: Compounds derived from areca nuts could help cigarette smokers quit. view more

Credit: Courtesy of Roger Papke, Ph.D.

SAN FRANCISCO, April 5, 2017 -- As many as 600 million people in Southeast Asia chew areca nuts with betel leaves, sometimes adding tobacco leaves. Many users are addicted to this harmful "betel quid" preparation, which can create a sense of euphoria and alertness. Yet researchers have now discovered that compounds derived from the nut could help cigarette smokers -- as well as betel quid chewers -- kick their habits.

The researchers will present their work today at the 253rd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world's largest scientific society, is holding the meeting here through Thursday. It features more than 14,000 presentations on a wide range of science topics.

"There's a commonality to the two addictions, so we thought we could develop drugs that target both," says Roger L. Papke, Ph.D., one of the lead researchers on the project. Fellow lead researcher Nicole A. Horenstein, Ph.D., and Papke, along with Clare Stokes and Marta Quadri, Ph.D., are studying compounds from the areca nut to make new molecules that might work better than existing smoking cessation drugs such as Chantix® (varenicline).

More than 480,000 people die each year in the U.S. from the effects of cigarette smoking, according to the U.S. Centers for Disease Control and Prevention. Prescription smoking cessation drugs currently on the market can work well but can also cause harmful side effects. For example, some patients taking the drug varenicline report having suicidal thoughts, sleepwalking and having cardiovascular problems.

Because of varenicline's side effects, researchers such as Papke and Horenstein are working on alternatives at the University of Florida. Varenicline reduces nicotine cravings by binding to the same receptors that attach nicotine molecules to brain cells, but it activates those receptors to a lesser degree. Undesirable effects occur because the drug also binds to other nicotine receptors that aren't involved in addiction, Papke explains. "The molecules that we're developing are more specific -- they do not target those other receptors at all, so our compounds should be safer," he says.

The idea to study the areca nut came when Papke obtained a headhunter's sword from Borneo. He learned that the peculiar carvings on its hilt might have been made by someone using betel quid. Quids are prepared by mixing sliced areca nuts with slaked lime (calcium hydroxide), spices or sweets, and in some cases tobacco, and wrapping the concoction in leaves from the betel vine. Quid chewing turns users' teeth bright red and forces them to spit out a lot of red saliva, which discolors local sidewalks and buildings. Worse, quid use is addictive and leads to serious health effects including oral cancer and cardiovascular issues.

In prior work (click here for a video), Papke and Horenstein studied arecoline, one of the psychoactive alkaloids in the areca nut. They discovered that arecoline stimulates the same brain cell receptors responsible for nicotine addiction but doesn't stimulate the other types of nicotine receptors.

Now, Horenstein is synthesizing a range of compounds with structures that are slightly different from arecoline. The researchers have found that some of these new compounds also bind to the addiction-related receptors, while leaving the other receptors alone. That means these arecoline analogs may be able to treat addiction to cigarettes or to betel quids without side effects. The next step for Horenstein and Papke is to seek funding so they can test these potential new drugs in animal trials.

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A press conference on this topic will be held Wednesday, April 5, at 10 a.m. Pacific time in the Moscone Center. Reporters may check-in at the press center, South Building, Foyer, or watch live on YouTube http://bit.ly/ACSLive_SanFrancisco. To ask questions online, sign in with a Google account.

The researchers acknowledge funding from the U.S. National Institutes of Health.

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Title

Selective nicotinic acetylcholine receptor activities from the areca nut

Abstract

The Areca nut is well known in southeastern Asia as the source of muscarinic active alkaloids that constitute a popular addictive drug known as the betel quid, in which limed extracts of the nut are rolled in betel vine leaves and in some cases, include tobacco. Of the four known alkaloids in Areca, arecoline is the most active muscarinic agonist while guvacoline is less potent. Arecaidine is an M2 selective agonist. Muscarinic activity has not been reported for guvacine, a GABA transport inhibitor. Two electrode voltage clamp electrophysiology experiments in Xenopus oocytes expressing muscarinic or nicotinic receptors have revealed that in addition to muscarinic activity, arecoline displays weak nicotinic partial agonism with a selectivity profile favoring α4β2 and α6β2β3α4β2 subtypes considered as targets for therapeutics aimed at nicotine addiction, while avoiding α7, α3β4, and muscle-type nAChR. This is in contradistinction to the known therapeutics cytisine and varenicline which although capable of partial agonism at α4β2 and α6β2β3α4β2 receptors, are strong agonists of the α7 receptor, and show significant activity at ganglionic α3β4 receptors. The arecoline analog isoarecolone shows an even more pronounced selectivity for α4β2 and α6β2β3α4β2 receptors compared to arecoline. It is noteworthy that whereas arecoline shows significant muscarinic activity, primarily at M1 mAChR, isoarecolone has nearly abolished activity at M1 and significantly reduced mAChR activity in assays against co-expressed M1, M2, and M3 receptors. Isoarecolone thus represents an interesting template for the development of new agents targeting α4β2 and α6β2β3α4β2 receptors. Interestingly we have found that Areca extracts also demonstrate an inhibitory component acting at nicotinic receptors. Fractionation based on size revealed that while both mAChR and nAChR activities resided in the low molecular weight fraction < 1 kDa, the inhibitory component was large with an estimated size > 10 kDa. These results will be discussed in the context of development of new therapeutics aimed at smoking cessation.

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