Conditions characterized by dopaminergic deficiencies can be treated by the administration of L-DOPA, a dopamine precursor that is converted to dopamine by DOPA-decarboxylase. Both endogenous dopamine and xenobiotic-derived dopamine are metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). COMT can also methylate L-DOPA to produce a non-active metabolite, preventing the conversion of L-DOPA to dopamine. The targeted inhibition of COMT can prolong the effectiveness of L-DOPA treatments by preventing premature metabolism of L-DOPA peripherally and of dopamine centrally. A series of catecholinergic and catecholic derivatives have been synthesized and analyzed in an enzymatic assay in order to determine the molecules’ inhibitory capacity. All ligands examined in the assay were also studied through in silico modeling, providing a computational determination of binding capacity to which the experimentally measured affinities can be compared. Specifically, this investigation focuses on the synthesis of catecholic derivatives with nitrile substituents, including 3,4-dihydroxybenzonitrile, 2-(3,4-dihydroxyphenyl)acetonitrile, and 3-(3,4-dihydroxyphenyl)propanenitrile. The nitrile derivatives were analyzed, along with dopamine and other, previously synthesized derivatives, in an assay with catechol-O-methyltransferase and co-factor S-adenosyl-L-methionine to experimentally determine the binding affinity and, subsequently, the inhibitory capacity of the proposed derivatives in relation to the binding affinity of dopamine.

Synthesis and analysis of dopaminergic derivatives as inhibitors of catechol-O-methyltransferase

251st National Meeting (2016)

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