Understanding the mechanisms of functionally selective drugs - Implications for new generation antipsychotic drugs

Associate Professor Chao Deng

Anti-psychotic drugs have improved the lives of schizophrenia patients around the world, yet these drugs also have debilitating side effects.

A major side effect of some newer generation antipsychotic drugs is the impairment of the body’s metabolic system, resulting in patients gaining large amounts of excess body weight.

The ability to continue to effectively treat the symptoms of schizophrenia, but prevent the associated side effects, is the focus of IHMRI's Antipsychotic Research Laboratory, headed by Associate Professor Chao Deng.

Creating pharmaceutical treatments with significantly reduced, or no side effects, relies on removing the ‘cause and effect’ of antipsychotic drugs on certain cellular signalling pathways in the brain.

Broadly, traditional drugs either stimulate or block receptors in the body. This affects the global signalling duties linked to that receptor, which normally produces the desired therapeutic effect, plus the undesirable side-effects.

Functional selectivity, however, may activate divergent signalling pathways through a single receptor (but not the global effects), potentially providing a route to separate the desired therapeutics from undesired side-effects.

Deng and the team at IHMRI have been the first to study the mechanism of an existing anti-psychotic drug with some known, but not well understood, functional selective properties in vivo – a major breakthrough.

Although the functionally selective properties of Aripiprazole had been reported previously, the only studies of its mechanisms had been in cell cultures, not in the complex in vivo environment of a living system.

Through in vivo studies, Deng will be able to better understand the mechanism of this drug’s functionally selective properties in humans, and hopefully apply the findings to new therapeutics that have limited or no side-effects.

He is optimistic about what this achievement will mean for the field of functional selectivity and for schizophrenia patients, in the short and long term.

“At the same time as having a long term goal of developing a new drug without major side effects, in the short term our goal is to reduce the negative side effects of current drugs.

“In parallel with the functional selectivity study, we have another path where we are providing evidence for a treatment approach that combines ariprprazole with other anti-psychotics as an effective way of reducing some side effects.”

“Improving the treatment outcomes for patients of schizophrenia now, while laying the groundwork for a potential new generation of antipsychotic drugs based on the principle of functional selectivity, is our end goal,” Deng says.

From IHMRI News Autumn 2011