A new method that allows synthesizing and purifying compounds of methylphenidate could pave the way for discovering cocaine-replacement therapies.
Researchers say the novel method could also be used in creating medications for central nervous system disorders (CNS), including epilepsy and Parkinson’s disease.
Methylphenidate (MPH; Ritalin®), a common drug for attention-deficit/hyperactivity disorder (ADHD), has been studied as a possible cocaine-replacement therapy because it increases dopamine levels in the brain by blocking dopamine reuptake the same way as the illicit drug. Additionally, it carries a lower risk of abuse than cocaine.
While animal studies have shown that MPH can reduce cocaine dependence, research in humans has offered more mixed results. Therefore, researchers are developing libraries of MPH derivatives to find molecules with improved clinical efficacy.
Despite several labs having produced MPH derivatives for testing, it was especially difficult to create derivatives of one chemical component of MPH: the piperidine ring. To address this shortcoming, the authors of the study published in ACS Central Science took an organometallic approach.
Using a tungsten-based reagent, the researchers synthesized a library of MPH analogs specifically modified at the piperidine ring with various chemical groups.
As MPH is a mixture of four isomers — otherwise identical molecules with small structural differences — the new method allowed the researchers to synthesize and purify compounds that were predominantly comprised of a single isomer.
Walter Dean Harman, an author of the study and professor of chemistry at the University of Virginia, says that it is yet to be seen what impact the findings will have on the development of cocaine addiction drugs.
"Our research provides a route to a new class of molecules that have many features similar to MPH. The likelihood that they are biologically active is high, but whether they will be effective in the treatment of cocaine disorders is a more difficult question. The important point here is that new chemical reactions lead to new compounds and many new compounds are needed to be able to discover new pharmaceuticals," he told Healthnews.
According to Harman, the new method provides a novel route to piperidines, which are very common structural components. Thus, a modified version of any existing drug with a piperidine ring could be prepared by this method.
Possible conditions that could respond to such compounds include most notably CNS disorders, such as headaches, chronic pain, epilepsy, Parkinson’s disease, cerebral palsy, addictions, autism, ADHD, and others.- Harman
Nearly 25,000 Americans died of a cocaine-related overdose in 2021, the Centers for Disease Control and Prevention (CDC) data shows. Despite many years of research, there are still no approved medications for cocaine dependence, whereas standard psychosocial treatment is inadequate for many patients.
Studies suggest that parapanol, a drug for high blood pressure, may lower cocaine withdrawal symptom severity and help to achieve an initial period of stable abstinence. GABAergic medications, such as anticonvulsants tiagabine and topiramate, also showed promise in clinical trials.
In several studies, a common treatment for alcohol use disorder, disulfiram, reduced cocaine use in patients with dependency on the drug, but the mechanism is not yet understood.
Although further investigation is needed, the new method to synthesize and purify MPH compounds could help to discover new pharmaceuticals for cocaine addiction and central nervous system disorders.
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- National Library of Medicine. New Medications for the Treatment of Cocaine Dependence.
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- National Library of Medicine. Novel approaches to the treatment of cocaine addiction.
- NEJM Journal Watch. Predicting Response to Disulfiram for Cocaine Use Disorder.