Drug Receptors May Be Multifunctional

The established "lock and key” theory of drug action may have to be modified, according to new research suggesting that all "locks” are not the same due to a newly described molecular mechanism called functional selectivity. This mechanism is described in two reports appearing in the June 1, 2002, issue of the Journal of Pharmacology and Experimental Therapeutics.

Investigators at the University of North Carolina (Chapel Hill, USA; www.unc.edu) designed several novel drugs, including dihydrexidine and propyldihydrexidine that mimic dopamine by binding to dopamine receptors in the brain. The assumption was that any drug binding to the dopamine receptor would act as an agonist--causing the same effects as dopamine--or as an antagonist, blocking dopamine's effects.

Instead of this simple black or white behavior, the researchers found that the drugs being tested acted as both agonists and antagonists. In the rat brain and pituitary, these drugs acted as agonists, like dopamine, in activating some functions. Yet the same drugs could also be antagonists, blocking dopamine-like activity, for other functions controlled by the very same dopamine receptors.

"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,” explained Dr. Richard Mailman. "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.”

The researchers speculate that the factor controlling the different drug effects may be the G proteins, signaling proteins required for receptor function. The different G proteins may serve as the doors in which the lock or receptor is installed, where it awaits 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,” added Dr. Mailman. "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.”




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