HOMA - homoamphetamine derivatives as partial releasers

The efficacy and mode of action of established bioactive molecules are, by virtue of in-depth studies, well understood, whereas the biological effects of slight alterations to the chemical structure are often unknown. Thus, even the slightest structural modifications hold promise for the study of alternative targets and treatments. Among such possible changes, homologation (i.e., the introduction of a single additional carbon atom) is one of the conceptually simplest approaches. Yet, preliminary results from our groups have indicated that the homologation of the carbon chain of classical amphetamines holds promise for the induction of partial efficacy, a trait that has the potential to lead to amphetamine derivatives of altered activity. We have therefore proposed the synthesis and in-depth evaluation of a range of homologated amphetamine derivatives through a hydroaminomethylation method recently reported by us. This novel approach, relying on the reaction of alkenes (an abundant feedstock material), a formaldehyde equivalent, and simple amine starting materials, will allow the rapid build-up of a library of homoamphetamines ready for biological testing. Structural variation will allow the determination of a structure-activity relationship, which will guide further iterations of synthesis, ultimately culminating in the identification of structures capable of selectively eliciting partial-releaser activity at defined monoamine transporters. The effect of stereochemistry will also be evaluated, as different isomers of related compound classes are known to show varying levels of activity. In order to achieve this, we will establish new methods for the enantioselective hydroaminomethylation of alkenes. This research project aims to synthesize, identify and fully characterize, through a systematic and co- operative investigation, partial releasers at monoamine transporters. The knowledge gained through this project will aid the understanding of monoamine transporters and facilitate the development of pharmaceuticals with increased selectivity and safety.