"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," said Dr. Richard Mailman, principal investigator. "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."

Two new papers just published by the team show that several drugs they designed have this property in intact brain, as well as in isolated nerve cells. The drugs used in the studies mimic dopamine, a transmitter that plays a vital role in several neurological and psychiatric diseases including schizophrenia and attention deficit disorder.

In both studies, the team designed several novel drugs, including dihydrexidine and propyldihydrexidine, that mimic dopamine by binding to dopamine receptors. Under accepted theory, such a drug would function either as an agonist or an antagonist, Mailman said. However, the investigators found that the drugs acted as both an agonist and an antagonist. Results involving the rat brain and pituitary found that the drugs acted as an agonist. However, the same drug acted as an antagonist for other functions controlled by the 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 intact brain studies: the drugs acted as both agonists and antagonists in different cell functions regulated by the same receptor.

Members of the team believe the basis for 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 actual "doors" in which the "lock," or receptor, is installed, awaiting the "key," or drug.

"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.