Research Looks to Reduce Side Effects of Medications for Depression, Addiction, Disease

A University research team is attempting to unravel the regulation of dopamine that leads to happiness. But happiness alone is not at the end of their search. The modulation of neurotransmitters dopamine, serotonin and norepinephrine in the synaptic cleft, or space, is at the heart of many health issues: substance abuse, schizophrenia, anxiety, Parkinson’s disease, attention deficit disorder, and depression. Medications may ease symptoms, but the team is also looking to reduce adverse side effects.

Dr. Jeffry D. Madura, professor of chemistry and biochemistry and a computational chemist in the Bayer School, is on the case with colleagues Dr. Christopher Surratt, professor of pharmacology; Dr. David Lapinsky, assistant professor of medicinal chemistry; and Dr. Michael Cascio, associate professor of chemistry and biochemistry. They are armed with 3-D computer modeling, pharmacology, medicinal chemistry, mass spectrometry and Madura’s $288,000-grant from the National Institutes of Health and National Institute on Drug Abuse for CRCNS: Computational and Experimental Study of Dopamine and Serotonin Transporter.

By mapping how these critical neurotransmitters are controlled, they are trying to better understand the function and structure of the proteins that modulate the receptor/transporter processes of dopamine and serotonin as well as amphetamines and cocaine. The group already has identified a compound as a potential new class of serotonin inhibitors. But to understand their work is to learn about the signaling process.

For instance, if your brain sends a “be happy” signal, dopamine molecules are released from the pre-synapse into the synaptic cleft, then matched with a receptor on the post-synapse, carrying along the happy message. This takes place in the flash of less than one millisecond.

But the “be happy” signal stalls when not enough dopamine is in the synaptic cleft or when the receptors become desensitized from too much dopamine in the synaptic cleft. The amount of dopamine in the synaptic cleft is, in part, controlled by a protein in the pre-synapse called a transporter. It shuttles dopamine from the synaptic cleft into the pre-synapse. The transporter malfunctions when cocaine is present; cocaine plugs the transporter, preventing dopamine from leaving the synaptic cleft and returning to the pre-synapse.

That’s where Madura and his colleagues step in. With virtual screening, which consists of building a model to screen compounds for potential serotonin transporter inhibitors, Madura and his team are searching for new antidepressant medication candidates.

“What is the order of what happens when a transporter moves a molecule from the synaptic cleft to the pre-synapse?” Madura asked. “We are analyzing molecular dynamic simulation results to understand the connections between the different transport steps.”

The team has created seven simulations of what dopamine transporters likely will do and are analyzing this data for an overall picture of the transport process.

“From these results, we can propose physical modifications on the transporters that can be experimentally tested. We want to see if we can turn the transporters on or off, or if we can trap the transporters in a particular state,” Madura explained. “We want to establish new types of scaffolds upon which new drugs can be designed that will reduce the adverse side effects of current antidepressants.”

Their initial findings were reported in the Biophysical Journal at the end of 2012, with their detailed analysis expected to be published by year’s end.