Duquesne research attempts to reduce side effects

By Victor Essel | The Duquesne Duke

A team of researchers at Duquesne is attempting to reduce the adverse side effects caused by medications that treat depression, addiction and neurological diseases.

Through its discoveries, the team has a better understanding of monoamine transporters: dopamine, serotonin and norepinephrine receptors. The new information could lead to the creation of better antidepressant medications as well as improved ways to treat addiction problems.

The team, consisting of chemistry professor Jeffry Madura, pharmacologist Christopher Surratt, assistant professor of medicinal chemistry David Lapinsky and associate professor of chemistry and biochemistry Michael Cascio, has developed new research of these monoamine transporters.

The modulation of dopamine, serotonin and norepinephrine in the synaptic cleft, or space, helps prevent substance abuse, schizophrenia, anxiety, Parkinson’s disease, attention deficit disorder and depression. Medications may ease symptoms, but could result in damaging side effects, which the team is looking to reduce.

“If everything goes well, our new findings could possibly be published in the early fall,” Madura said. “This information has the potential to become lead components in the development of new antidepressants.”

Madura said the team’s goal is to “understand the structure, function and dynamics” of the transporters at the atomic level and “to use this knowledge for the design of new therapeutic drugs.”

“We’ve identified a new scaffold of molecules to act as an inhibitor,” Madura said. “Finding an inhibitor was important. It is something that stops the transporter from functioning. During our research, we realized there are two places in the transporter that we could design inhibitors.”

The University team of professors combined computational, pharmacologic, medicinal and biophysical methods of research to contribute to the discovery of new insights.

“The monoamine transporters are responsible for transporting molecules across membranes – specifically neurons. They play an important role in our moods, appetites, and emotions,” Madura said.

“[The Transporters] play an important role in our moods, appetites and emotions.”

Jeffry Madura

Pharmacologist

Cascio came to Duquesne in 2009 after 15 years at the University of Pittsburgh. As a biophysicist, he looks at the structure of the molecules, contributing to the research team from a biophysical perspective.

“Madura works with computational methods to produce models that identify binding sites. We take this information, and carry out experiments on actual binding sites,” Cascio said.

After the physical experiments are completed in the lab, Cascio said the team either validates or refines the virtual models.

“We want to tweak the information so that we can have a better understanding of how specific drugs react with receptors,” he said.

Cascio said the team has worked with common antidepressants such as Citalopram and Fluoxetine, better known by the brand names Celexa and Prozac respectively. All of these drugs are related to monoamine transporters.

Madura said these dopamine and serotonin transporters are involved with a complex pathway, or network, which are directly related to neurological diseases such as depression.

According to Madura, plans for the research started in 2007, but it was first funded in 2009 by various National Institute of Health grants. Madura, along with Lapinsky, Cascio and Surratt are funded by the NIH.

“The grants helped us to build off of previous research,” Madura said.

The research began when Surratt wanted to apply computational methods in the search for a compound that would displace cocaine in the dopamine transporter while restoring normal dopamine transport, according to Madura.

“The development of 3D models of the monoamine transporters is extremely important for research,” Madura said. “The 3D models allowed us to identify a secondary binding pocket that is different from the primary substrate-binding pocket. Our 3D models are used in virtual screening studies to identify novel monoamine transporter inhibitors.”

In the case of the dopamine transporter, Madura has found a compound that displaces cocaine and partially restores re-uptake of dopamine. He has also found novel serotonin transporter specific inhibitors.

“This is one small part of several parts of the project,” Madura said. “The research will continue for five more years, at the least.”

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