Robert Huigens, Ph.D., an assistant professor of medicinal chemistry, has re-engineered the structure of vincamine, a plant-derived compound, and administered it to mice, successfully reducing their morphine-seeking behaviors. The American Chemical Society featured the study on the May cover of the Journal of Medicinal Chemistry.
Many plant-produced compounds have complex structures that can bind to therapeutically relevant biological targets. Huigens hypothesized that by altering the structure of vincamine — an indole alkaloid from the leaves of the plant Vinca minor — they could obtain a molecule that binds to new protein targets involved in opioid addiction, blocking drugs’ high sensations.
The team altered vincamine’s chemical structure, producing a diverse library of 80 small molecules. They then screened seven of these molecules for the ability to bind to certain protein receptors and block their action. One of the molecules, which they refer to as “V2a,” inhibited a protein called hypocretin receptor 2 that is involved in heroin dependence, whereas the parent compound, vincamine, had no effect.
The researchers then tested this compound in mice, finding that pretreatment with V2a prevented mice from spending extra time in a chamber where morphine is administered. In another experiment, mice that had “recovered” from morphine addiction, and then were treated with V2a, did not relapse to morphine-seeking behaviors in response to stress, unlike mice that were not treated with the new molecule. The team also conducted molecular modeling experiments to visualize how the compound binds to HCRTR2, which could allow them to tweak the structure of the compound for even stronger binding and efficacy.