For a couple of thousand years, smokers have sought a quick concentration boost by firing up a cigarette.

It turns out that cognitive buzz isn’t just in smokers’ heads. Scientists have found that nicotine really does boost certain transmitters in the brain that can help people think better. Now, the pharmaceutical industry hopes to improve on the effect, minus the lung cancer.

Earlier this summer, biopharmaceutical company Targacept reported that a compound called ispronicline acted like nicotine to increase memory and concentration in elderly test subjects. Targacept next plans to test the drug on people with Alzheimer’s disease.

If successful, ispronicline will be at the head of a whole new class of drugs that target neuronal nicotinic receptors. The receptors, found on nerve cells in the brain, respond to two chemicals: acetylcholine, which is found naturally in the brain, and nicotine.

“They’re like volume knobs for the brain,” said Merouane Bencherif, Targacept’s vice president of preclinical research.

Nicotinic receptors affect almost every human function, including movement, breathing and even mood, which means the potential treatments from a drug that alters the receptor could range widely from Alzheimer’s and Parkinson’s to depression and schizophrenia.

While nicotine can take acetylcholine’s place in binding to nicotinic receptors, it’s only a rough substitute.

“It’s a very poor mimic,” said Roger Papke, a nicotinic receptor researcher at the University of Florida.

“Nicotine activates the receptors for a time, but then deadens them for a longer period of time. There are also many different types of nicotinic receptors, and nicotine doesn’t specify. It’s what I call a dirty drug,” Papke said.

Only in the last couple of decades have scientists figured out how nicotine works in the brain. While nicotine is not responsible for the cancers caused by cigarettes, it can cause increased heart rates and respiratory problems. And, of course, it’s addictive.

“Pharmaceutical companies are developing compounds that have the beneficial — but not the toxic — properties of nicotine, and selectively act on a subset of the different nicotinic receptors in the brain,” said J. Michael McIntosh, a University of Utah neuroscientist.

Scientists think ispronicline might treat Alzheimer’s because the disease has been linked to acetylcholine deficits in animals. Nicotinic drugs have already been effective in treating acetylcholine-deficient animals, Papke said.

While Alzheimer’s appears to be the most immediate therapeutic target, there are many more, including Tourette’s syndrome, Lou Gehrig’s disease, schizophrenia, depression and anxiety. Neuroscientists think nicotinic drugs could even treat the cognitive difficulties of aging.

“One of the things that happens in both aging and Alzheimer’s is that cells start to die,” Papke said. Stimulating certain nicotinic receptors appears to prevent this death — and that, said Bencherif, is “the holy grail” of such therapies.

Best of all, said Jerry Buccafusco, a neuropharmacology professor at the Medical College of Georgia, the therapies will not simply be surface treatments. “At least some of them have the potential not just to relieve symptoms, but to modify the disease,” he said.

Another type of nicotinic receptor is found in muscles, which leads scientists to believe that nicotinic drugs could also treat inflammatory diseases and relieve pain — possibly replacing opiate-based analgesics like morphine and oxycontin, which are addictive and often dangerous.

With so many therapeutic possibilities, the nicotinic drug field is crowded by pharmaceutical companies in various stages of research and development.

Abbott Laboratories is testing one compound on Alzheimer’s, attention deficit hyperactivity disorder and schizophrenia, and another for pain relief. Merck, AstraZeneca, Bristol-Meyers Squibb, Eli Lilly, sanofi aventis, Memory Pharmaceuticals, Critical Therapeutics and Pfizer are also developing nicotinic drugs.

Pfizer’s drug, Varenicline, intended to help people quit smoking, is in Phase III clinical trials. Buccafusco thinks the nicotinic floodgates will open once Varenicline hits the market.

“Nicotinic drugs,” he said, “could be not just a major improvement, but a quantum improvement in the tools physicians have to treat disease.”

By Brandon Keim

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