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OHSU lab finds meth receptor that could lead to therapy

April 19, 2007

TAAR1 could become target to reverse drug's effects

PORTLAND, Ore. — A recently discovered signaling system in the brain has just been shown to be turned on by methamphetamine, an Oregon Health & Science University study found.

The signaling system could soon become a target for therapies aiming to reverse meth's adverse health effects as well as reduce the craving that drives its abuse.

Working in the recently opened Program in Chemical Biology in the OHSU School of Medicine's Department of Physiology and Pharmacology, scientists demonstrated the new target of meth, and its close relative amphetamine, is a G protein-coupled receptor known as trace amine-associated receptor 1, or TAAR1 for short.

"The Program in Chemical Biology at OHSU is one of the few in the U.S. that allows biologists and chemists to work side-by-side, using their combined skills to identify drug targets and to design new drugs to treat diseases like drug addiction," said David Dawson, Ph.D., OHSU professor and chairman of physiology and pharmacology. "Chemical space - that is, the number of possible drug molecules that could exist - is incredibly large. Our aim is to mine that space in order to uncover novel therapies."

TAAR1 was originally discovered in the laboratory of David K. Grandy, Ph.D., OHSU professor of physiology and pharmacology. Grandy's lab found TAAR1 is activated by chemical relatives of meth known as phenylethylamines. The messenger RNA that codes for TAAR1 is expressed throughout the brain, including areas involved in motivation and drug craving, olfaction - the sense of smell - and temperature regulation, to name a few.

"With this kind of pharmacological profile and brain distribution, we hypothesized TAAR1 could mediate some of meth's metabolic and behavioral effects," explained Grandy, who also directed the groundbreaking research.

"In our most recent article, we provide clear evidence that methamphetamine is a full and potent agonist of TAAR1. In other words, TAAR1 has the necessary features to be considered a real target of methamphetamine and amphetamine in rodents and probably humans, too."

Grandy added that it's his hope that "these findings will eventually lead to the development of new pharmaceuticals that reduce dependence on and craving for methamphetamine."

The study is published in the April edition of the Journal of Pharmacology and Experimental Therapeutics.

Earlier research in the Grandy laboratory demonstrated that meth and amphetamine stimulate the production of an important second messenger known as cyclic adenosine monophosphate, or cAMP, inside cells expressing the rat TAAR1. Encouraged by this observation, Grandy's team explored the effects of these drugs on mouse TAAR1 and a human-rat TAAR1 hybrid and found all three receptors respond in similar ways.

"The results of this study unequivocally demonstrate that meth and amphetamine are able to directly activate this receptor in the laboratory, making it likely that TAAR1 is activated in chronic users of meth," the researchers state in their article, whose lead author is Edmund Reese, a graduate student working in Grandy's laboratory. Other members of the research team include James Bunzow, M.S.; Seksiri Arttamangkul, Ph.D.; and Mark Sonders, Ph.D.

Grandy and his colleagues argue that TAAR1 represents a completely new target for pharmaceutical therapy to treat meth addiction and also reduce the negative manifestations of its abuse.

"Meth addiction is such a problem and we have nothing to treat it with except group support therapy," Grandy said. "Now we have a new target, something completely different to focus on, and we think that offers a lot of hope."

Grandy is actively collaborating with Thomas Scanlan, Ph.D., director of the Program in Chemical Biology who recently relocated to Portland from the University of California, San Francisco. Scanlan's laboratory has synthesized more than 150 new compounds that are being analyzed for their ability to selectively interfere with TAAR1 and block its activity.

"So we're already on a roll," Grandy said. The goal is to "take them to the point where they can be tested in humans."

Still, there's more to be learned about how meth and amphetamine affect the entire TAAR1 signaling system that is composed of six receptor genes in humans. "When you put it all together, what you realize is that meth acts on several signaling systems and that a successful therapeutic treatment will likely require modulation of several targets simultaneously. We still have a lot to learn about how meth affects the body through this system," Grandy said. "We have our work cut out for us."

Oregon Health & Science University