Assay tests documented in PNAS show that nine drugs block G-protein pathway inconsistently.

Some antipsychotic drugs do not work as scientists have assumed, according to researchers from Duke University Medical Center. Their studies covered nine drugs that work through the G-protein-dependent signaling pathway or the beta arrestin pathway, both targeting the D2 receptor inside cells.

The investigation determined that the drugs had different profiles for the G-protein pathway. Some activated it, some blocked it 50%, and some blocked it entirely.

The work showed, however, that all nine antipsychotic drugs examined uniformly and more potently block the beta-arrestin pathway downstream of the D2 dopamine receptor.

Since G-protein coupled receptors have been the most common target of such therapeutic drugs, “drug manufacturers would want to make sure new compounds for antipsychotic use block the beta-arrestin pathway,” says Bernard Masri, Ph.D., lead author and postdoctoral researcher in the Duke Department of Cell Biology.

The team used a bioluminescence resonance energy transfer (BRET) technique to monitor specific receptor signaling pathways. One assay followed the variation of cyclic adenosine monophosphate to look at the G-protein dependent pathway, and the other measured the direct interaction of beta arrestin with the dopamine D2 receptor. The antipsychotics were tested on both assays to look at how well they were activating or blocking particular pathway(s).

The next project for the scientists is to study these drugs and the relevant pathways in both normal mice and mice with traits of psychosis.

Findings are published in this week’s issue of the Proceedings of the National Academy of Sciences.

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