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Faculty Entrepreneurs
Linda Dwoskin & Peter Crooks: Some Research Findings to Crow About

by Jeff Worley

A rooster got Linda Dwoskin excited about science.

"In fourth grade I did a school report on why roosters crow in the morning. I found out that they crow because light hits their retina and sends signals to the brain. That early 'investigative science' got me hooked."

As a student Dwoskin followed this interest to Georgia Tech ("the ratio of men to women was 40-1 in those days"), and then to Syracuse University, where she earned a B.S. in psychology, and then to the University of Minnesota for her graduate work. With a Ph.D. in pharmacology from the University of Minnesota under her belt, she did two postdocs before coming to the University of Kentucky in 1988, where she is now an endowed full professor in the College of Pharmacy.

Although that rooster's wake-up call is merely a vague memory now, Dwoskin is still focusing her research on the inner workings of the brain, specifically how to block the "highs" of drugs such as methamphetamine.

"For the past eight years or so, I've been working on a compound that was initially thought to act like nicotine, my research 'drug of choice' since coming to the University of Kentucky. The name of the compound is lobeline, an alkaloid [an organic base that can be used as scaffolding to make useful drugs] from American Indian tobacco," she explains. "This plant grows up and down the eastern seaboard, and though it is generally considered to be a weed, it produces pretty blue flowers."

In previous published studies, scientists characterized lobeline as a nicotinic agonist, a chemical substance like nicotine capable of combining with nicotinic receptors on cells, which triggers a reaction. So lobeline was lumped into the same pharmacological category as nicotine.

"But lobeline did not behave like nicotine, so we took a fresh look at it," says Dwoskin. "We discovered that lobeline acts as a nicotine antagonist—the opposite of what people had thought." Dwoskin, in collaboration with Peter Crooks, a medicinal chemist who is also an endowed professor in UK's College of Pharmacy, and Michael Bardo, a professor in the Department of Psychology, found that lobeline, in fact, blocks both the behavioral and neurochemical effects of methamphetamine, a startling and potentially breakthrough discovery that could lead to effective drug-abuse treatment.

Crooks, who came to UK from the U.K. (University of Manchester) in 1981, says that their collaboration "is a shining example of how university pairings can have unexpected but happy results." Crooks had been working on nicotine for several years when Dwoskin joined the faculty and "got into nicotine, since Kentucky is a tobacco state and tobacco is a highly addictive stimulant." This scientific partnership has led to, among other findings, the discovery of lobeline's actual chemical role and its potential for treating drug abusers.

Bardo, who has conducted animal behavioral studies with lobeline, found that when rats that press levers to obtain methamphetamine intravenously are pre-treated with lobeline, they don't want the drug anymore. "This was good—and very encouraging—evidence from animal studies as to the potential therapeutic efficacy of lobeline as a treatment for methamphetamine abuse," Dwoskin says.

Crooks, who has been involved in various entrepreneurial enterprises over the last 10 years, says that the next important step was to patent the idea that lobeline might be an effective treatment for psychostimulant abuse. "I found it very easy working through UK intellectual properties to do this," Crooks says. "Getting a patent always takes longer than you think it ought to, but it's obviously essential to do this."

Crooks says the next step was to write an article detailing their findings, which they did. The National Institute on Drug Abuse published "Lobeline Robustly Increases Tritiated Dopamine Release from Rat Striatal Slices" in 1994. "One nice result of this was a sizeable grant from the National Institute of Drug Abuse in the NIH," Crooks says, adding that the NIH has funded his and Dwoskin's work continuously since the early 1990s and that UK's Tobacco and Health Research Institute also funded the initial studies on lobeline.

Dwoskin and Crooks then decided to follow their research even further than either of them had, early-on, imagined: to form a company and sell this patented idea for treatment. Last September, Yaupon Therapeutics Inc. opened its doors in UK's Advanced Science and Technology Commercialization Center (ASTeCC). Yaupon, which means "tree leaf" in a Native American Indian dialect, is specializing in drugs drawn from natural products to treat a variety of disorders, especially those affecting the central nervous system. Yaupon, with 1,500 square feet of lab and office space, currently has nine employees and has already attracted significant funding from the NIH and seed investors.

"Our business is based on years of academic research that was just waiting for a commercial focus," says Robert Alonso, president and CEO of Yaupon. "We've joined scientific talent with business expertise, and we have access to resources at UK usually reserved for a top-tier pharmaceutical firm." Well, Alonso should know. He worked previously for the pharmaceutical giants Merck and Hoffmann-LaRoche.

Although the company, which is working in partnership with the university, is currently exploring the commercial potential of five compounds, the most advanced product in the company's pipeline is lobeline. The NIH sees such promise in this drug that it has already committed significant funding towards its development.

"The federal government is helping us develop lobeline for clinical use as a treatment for methamphetamine abuse, which is not only a terrific statement of support, but also a financial sigh of relief," Dwoskin says. "Clinical trials are a very expensive business."

"It's getting exciting," adds Crooks. "Through regular teleconferences going on now between Yaupon and NIDA, we're able to tap into the expertise there. We're hoping that with the federal government on board, that will accelerate things."