Catechol-O-methyltransferase (COMT) can deactivate L-DOPA and dopamine by transferring a methyl group from the co-factor S-adenosyl-L-methionine (SAM) to a hydroxyl group. L-DOPA is a dopamine precursor and is administered as a treatment for patients with Parkinson’s Disease to supplement dopamine levels. Methylation and subsequent deactivation of L-DOPA by COMT, along with deactivation by other enzymes, causes little of the administered dose to convert to dopamine in the brain. Therefore, competitive inhibition of COMT as a strategy to prolong L-DOPA effectiveness is attractive. Several dopamine derivatives and catecholic nitriles, with various groups at the 6th position, were synthesized following computational analysis and their inhibition was evaluated via fluorescence screening assay. Molecular docking studies and pKa values were conducted to further understand the behavior of these compounds with COMT. Catecholic nitriles with a nitro group at the 6th position showed the most potential as inhibitors of COMT. These results confirmed the computational predictions and illustrate that it is more than just the lowered pKa value or neutral tail that lead to strong inhibition.

Evaluating dopamine derivatives and catecholic nitriles as inhibitors of catechol-O-methyltransferase

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