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Link: www.fwf.ac.at/forschungsradar/10.55776/PAT1509823
Duration: 01.07.2024–31.12.2026
Funding amount: € 485.060
Project Partner: Prof. Harald H. Sitte (Medical University of Vienna)
Keywords: Amphetamine, Partial Releaser, Amines, Hydroaminomethylation, Pharmacology
Abstract
Wider research context: Structural modification of established bioactive compounds, as enabled by synthetic chemistry, holds the potential to change efficacy or target, thereby offering an opportunity to study alternative therapeutic strategies. In this regard, the countless established amphetamine derivatives have shown that alterations to the substitution pattern often elicit dramatic changes to the biological function. Initial results from our team indicate that, contrary to previous reports of inefficacy, homologation of the amphetamine chain may be capable of inducing partial efficacy at monoamine transporters (MATs).
Hypotheses and objectives: We will employ our original method to synthesize a wide range of homologated amphetamines (homoamphetamines), ultimately allowing us to study their releaser activity at monoamine transporters. Based on initial results, our hypothesis is that this variation to the core amphetamine structure holds the potential to create partial releasers, resulting in opportunities to fine-tune transporter-mediated efflux and maximize possible therapeutic efficacy. Crucially, further development of a previously reported amine synthesis through an alkene hydroaminomethylation reaction is necessary to introduce new structural motifs. We have also obtained initial evidence that the stereochemistry of homoamphetamines affects efficacy. For this reason, we aim to establish a novel, enantioselective approach to hydroaminomethylation, to aid in the study of stereochemical effects.
Approach and methods: We will combine several methods and approaches in an iterative strategy: organic synthesis will produce an array of diversely substituted homoamphetamines (including enantioselective synthesis), followed by a number of experimental in vitro approaches. Here, mainly tracer flux assays, electrophysiological approaches at the single-cell level, and toxicological assessment of the novel compounds will be deployed.
Level of originality and innovation: This proposal will enable the first systematic investigation of homoamphetamine derivatives as potential partial releasers at MATs. While alkene hydroaminomethylation already can generate such structures, the expansion of this approach to the incorporation of moieties of ever-increasing complexity promises to make available an entirely new synthetic path to not only homoamphetamines, but aliphatic amines in general. The development of an enantioselective approach, in particular, will constitute a significant innovation in the broad field of amine synthesis.