UNC studies add new dimension to 'lock-and-key' theory of drug action

May 30, 2002

CHAPEL HILL -- A scientific collaboration based at the University of North Carolina at Chapel Hill has broken new ground for future drug design and development for brain disorders such as Parkinson's disease and schizophrenia.

The team, headed by Dr. Richard Mailman, a professor at UNC's School of Medicine, has advanced a molecular mechanism called functional selectivity in connection with research shedding new light on the classic view of drug action called the "lock-and-key" theory. Under this decades-old idea, the best drugs will be "keys" that only fit a single biological target, or "lock."

"Our data now show that we must think not only of the 'lock' and the 'key,' but also about different 'doors' in which the locks are installed. The 'doors' are different organs, or even different parts of the same organs," Mailman said. "Scientists have assumed that one drug would fit and turn all of these identical locks in the same way. Our team's work shows that even though all of the locks may be the same, some keys may only open the locks on certain doors."

While scientists at several laboratories, including those at UNC, have suspected that the old lock-and-key idea was too simple, this belief was based on studies in isolated cells. Now, two new papers just published by Mailman's team show that several drugs they designed have this property in intact brain, as well as in isolated cells. The drugs used in the studies mimic dopamine, a neurochemical playing a key role in several neurological and psychiatric diseases including Parkinson's disease, schizophrenia and attention deficit disorder, he said.

The companion papers appear in the June 1 issue of the Journal of Pharmacology and Experimental Therapeutics, which is published by the American Society of Pharmacology and Experimental Therapeutics.

Team principals are Mailman, professor of psychiatry, pharmacology and medicinal chemistry, Dr. Gerry Oxford, professor of cell and molecular physiology, and Dr. R. Mark Wightman, professor of chemistry, all at UNC, as well as Dr. David Nichols, professor in the department of medicinal chemistry and molecular pharmacology at Purdue University, Dr. Richard Todd, Blanche Ittleson professor, and Dr. Karen O'Malley, professor of neurobiology, both of Washington University in St. Louis. Eight current or former UNC graduate students and postdoctoral fellows also contributed to the research.

In both studies, the UNC team designed several novel drugs, including dihydrexidine and propyldihydrexidine, that mimic dopamine by binding to a special type of protein called a dopamine receptor. Under accepted theory, such a drug would function either as an agonist -- causing the same effects as dopamine -- or an antagonist -- blocking dopamine's effects -- at any dopamine receptor and always act the same way, Mailman said.

The drugs used by the UNC team acted as both an agonist and an antagonist, he said. Results involving the rat brain and pituitary found that these drugs acted as an agonist, like dopamine, in activating some functions. Yet the same drug could also be an antagonist, blocking dopamine-like activity, for other functions controlled by the very same dopamine receptors.

To confirm the findings, the scientists then tested the drugs in the laboratory in a variety of systems in which the receptor targets could be carefully controlled, Mailman said. The team grew several types of cells and added dopamine receptors. The results mirrored those of the brain studies: the drugs acted as both agonists and antagonists in different cell functions regulated by the same receptor.

Members of the UNC team believe the key to the different effects relates to other signaling proteins, called G proteins, that are required for the receptors to function. The different G proteins may be the "doors" in which the "lock," or receptor, is installed, awaiting the "key," or drug, Mailman said.

"What makes this research noteworthy is that for the first time we were able to show that these mechanisms work not only in cells in the laboratory, but also in the mammalian brain," he said. "Such ideas have important implications for how scientists discover the next generation of drugs because they permit the design or selection of drugs with much more refined mechanisms of action."

Scientists may be able to take known targets and develop new drugs with much-improved clinical effects, Mailman said. "We believe that this mechanism is one key to the actions of a novel anti-schizophrenic drug originally developed in Japan and now awaiting final approval by the FDA," he said.
The National Institutes of Health supported the UNC team's research.

Drugs used in the studies and the technology upon which they are based, have been licensed by UNC and Purdue to DarPharma Inc., a biopharmaceutical start-up company in Chapel Hill begun last July based largely on 15 years of collaborative research by Mailman and Nichols. DarPharma is among about a dozen new UNC spin-off companies, which benefit the North Carolina economy by creating jobs and helping improve the quality of life for state citizens, university officials say.

Note: Contact Mailman at (919) 966-2484 or richard_mailman@med.unc.edu. Additional background is at http://research.unc.edu/endeavors/spr2002/mailman.html and http://www.darpharma.com/

News Services contact: Mike McFarland, (919) 962-8593, mike_mcfarland@unc.edu

University of North Carolina at Chapel Hill

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