Based on recent findings in experimental animals, there is growing concern that MDMA and fenfluramine may be toxic to serotonin (5HT) neurons in the human brain. Despite this concern. human use of MDMA and fenfluramine continues. MDMA is used as a recreational drug, and some mental health specialists claim it has psychotherapeutic utility. Fenfluramine is an anorectic agent. It is used in the treatment of obesity, and also in the therapy of autistic children. Recently, N-methylation has been found to selectively attenuate the 5HT neurotoxic activity of methamphetamine, a congener of MDMA and fenfluramine. The goal of this research is to test the hypothesis that N-methylation will also attenuate the 5HT neurotoxic activity of MDMA and fenfluramine without eliminating their behavioral activity. To this end, N-methylated analogs of MDMA and fenfluramine have been synthesized. Their identity and purity has been confirmed and pilot neurotoxicity studies have been carried out. These show that N-methylated analogs of MDMA and fenfluramine have reduced 5HT neurotoxic activity. In addition, preliminary behavioral studies suggest that these analogs retain pharmacological activity. The present studies will systematically characterize and compare the neurotoxic, behavioral, and biochemical properties of N-methylated analogs of MDMA and fenfluramine. Neurotoxicologically, combined chemical and anatomical methods will be used to assess the neurotoxic potential of these analogs. Behaviorally, their anorectic, reinforcing, psychomotor stimulant and discriminative stimulus properties will be investigated, and compared to that of their parent compounds. Biochemically,the metabolic fate of the various N-methylated analogs and their parent compounds will be characterized in vitro in an effort to identify important toxification and detoxification mechanisms. As part of this effort, metabolic intermediates will be synthesized, and their neurotoxic and behavioral profiles will also be investigated. The long-term objectives of this research are: 1) to develop non-toxic analogs of MDMA and fenfluramine which retain clinically useful pharmacological activity and 2) to use such analogs to delineate the mechanism of neurotoxic action of MDMA and related compounds.
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