Dopamine is a neurotransmitter essential for normal biological function of the brain and body. It is synthesized, stored in vesicles, and released into synapses by presynaptic neurons in dopaminergic pathways in the central nervous system. Receptors on postsynaptic neurons bind the dopamine and transmit a signal intracellularly through second messenger systems. The removal of dopamine from synapses is carried out by the dopamine transporter (DAT). Many neurodegenerative diseases are related to abnormal dopaminergic activity in the brain. Decreased levels of dopamine caused by the death of dopaminergic neurons leads to Parkinson’s disease, and the overactivation of certain dopamine receptors may cause the development of schizophrenia. Cognitive deficits occur in these and other psychological disorders, likely because of altered levels of dopamine and dopaminergic signaling in the prefrontal cortex. DAT inhibitors may be introduced into the synapse to prevent this reuptake of dopamine and to perpetuate cell signaling, which has been shown to be able to improve cognitive performance in animals and humans. Based on the structure of the putative binding site of dopamine in the DAT and the structures of other known DAT inhibitors, specifically methylphenidate, 3-(tert-butylamino)-2-phenylpropanoate esters were designed as potential novel DAT inhibitor molecules. The synthetic plan required only four transformations for each target molecule, with high to moderate yields of all intermediates. The syntheses of the methyl series and ethyl series are complete and work is continuing on the phenyl series, where an unexpected cyclization reaction has slowed progress on the enolate alkylation reaction. Pending pharmacological activity will provide valuable information on the structure-activity relationships of these series of molecules and contribute to the binding profile of inhibitors to DAT.

Design and synthesis of substituted 3-(tert-butylamino)-2-phenylpropanoate esters as potential dopamine transporter inhibitors

255th National Meeting (2018)

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