Preclinical medication development for stimulant use disorder

National Institute On Drug Abuse

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Linked publications & trials

Abstract

Summary- Significant progress was made on this project, which involves the development of medications for stimulant use disorders. Four relevant papers were published in peer-reviewed journals. In one especially interesting article, we report on the synthesis and characterization of a series of novel transporter ligands based on the (2-aminopropyl)benzothiophene (APBT) structural template. Two major groups of amphetamine-like compounds are based on the (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur-based analogs with a benzothiophene structure, resulting in (2-aminopropyl)benzothiophene (APBT) derivatives, have received little attention. In our investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure-activity relationships relative to API- and APB-based drugs. An in-depth analytical characterization was performed, including various single- and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC-sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non-routine conditions. Discriminating analytical features can also be derived from NMR, GC-EI/CI- single- and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC-sIR). Availability of detailed analytical data obtained from these novel APBT compounds will be useful to researchers and scientists who are interested in studying the pharmacology of novel transport ligands as potential medications.