Armed with more than $2.4 million in grants from the National Institutes of Health (NIH) and an innovative approach, a pharmacologist, a medicinal chemist and a computational chemist at Duquesne University have teamed up to look for a drug to fight psychostimulant dependence.
Specifically, they are seeking drugs to block the actions of cocaine and amphetamines, psychostimulants that have seen growing abuse nationwide.
While heroin addicts can use methadone or buprenorphine to ease withdrawal symptoms without providing the same level of dependence, nothing comparable is available to the estimated 1.9 million cocaine users nationwide or the 1.3 million people who have used methamphetamine.
“The top brass of the National Institute on Drug Abuse (NIDA) has described such an elusive anti-psychostimulant as the holy grail for the field,” said Dr. Christopher K. Surratt, division head of pharmaceutical sciences and associate professor of pharmacology at Duquesne who has been working on addiction issues since 1991. “We want a drug that interferes with cocaine action without being another cocaine.”
Surratt, Dr. David J. Lapinsky, assistant professor of medicinal chemistry, and Dr. Jeffry Madura, chair of the chemistry department, each received separate grants from the National Institutes on Drug Abuse, a branch of the NIH, to work on a multi-year project that uses a “rational design” drug discovery approach toward lessening the impact of cocaine and amphetamine addiction on individuals. In tackling this task, each professor has a distinct research area but coordinates efforts with the other two, magnifying and examining issues simultaneously. They also credited outstanding graduate alumnus, Martin Indarte, who played a critical role in receiving these grants.
The unusual triple-threat approach grew naturally from harnessing similar interests, similar goals and diverse skills—and reflects the recent emphasis of NIH on funding highly collaborative efforts, which was one consideration for the grants.
“You’d be hard-pressed to find another school with a teacher-scholar faculty model that has this,” Surratt said.
In their work, the researchers are first trying to determine exactly how, at the cellular level, cocaine and amphetamines bind to the dopamine transporter, a protein that shuttles the neurotransmitter dopamine across membranes. Dopamine controls movement, motivation, emotion and pleasure in the brain.
“Right now, there is no known experimental structure of a dopamine transporter,” Madura said. “We are using a computer-built, 3-D structure. We don’t know if what we have built is correct, so we need to validate our structure using the pharmacological results from Dr. Surratt’s laboratory.”
Only recently, have technological advancements allowed researchers to virtually model what happens at the lab bench, explained Surratt, who handles the neuroscience side of the project. “To have both computational and medicinal chemists in-house was perfect.”
Lapinsky, the medicinal chemist, examines the issue from the angle of creating compounds that can refine and validate the computer-generated model, ultimately leading to the discovery and development of new compounds that Surratt can test in his lab.
Through Madura’s“virtual screening,” millions of chemical compounds are filtered using the computer model to identify potential candidates that may block the cocaine “high.” The most promising compounds are then tested at the lab bench. Based upon the pharmacological findings, new compounds may be synthesized.
In this way, Madura eliminates much of the costly trial-and-error factor in drug discovery, saving both time and money. His work allows Surratt and Lapinsky to focus on compounds most likely to block the euphoria of cocaine.