Monday, August 25, 2008

Looking beyond the drug receptor for clues to drug effectiveness

Antipsychotic drugs that are widely used to treat schizophrenia and other problems may not work as scientists have assumed, according to findings from Duke University Medical Center researchers that could lead to changes in how these drugs are developed and prescribed.

Scientists have known that all antipsychotic drugs target the D2 receptor inside cells. New tests developed at Duke reveal that the biochemical pathways linked to this receptor – the pathways along which the drugs deliver their therapeutic effects – may function differently than previously understood.

The Duke team developed specialized tests and studied two main pathways that stem from the receptor. The first is the G-protein-dependent signaling pathway, and the other is the beta arrestin pathway.

Most antipsychotic drugs in use today were developed to target the G-protein signaling that occurs at the receptor. Only recently, beta-arrestin, a protein known as an "off-switch" for G-protein receptors, has been shown to also play a role in directing other cellular activities.

The tests uncovered surprising results. "Our work showed that all nine antipsychotic drugs we examined uniformly and more potently block the beta-arrestin pathway downstream of the D2 dopamine receptor," said Bernard Masri, Ph.D., lead author and postdoctoral researcher in the Duke Department of Cell Biology.


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