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

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 Parkinsons disease and schizophrenia.

The team, headed by Dr. Richard Mailman, a professor at UNCs 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 teams 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 Mailmans 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 Parkinsons 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.

Contact: Samantha Radel
University of North Carolina at Chapel Hill

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