l-DOPA, a dopamine precursor, is commonly used as a treatment for patients with conditions such as Parkinson's disease. This therapeutic l-DOPA, as well as the dopamine derived from l-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). Targeted inhibition of COMT prolongs the effectiveness of l-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Following the completion of a previous ab initio computational analysis of 6-substituted dopamine derivatives, several novel catecholic ligands with a previously unexplored neutral tail functionality were synthesized in good yields and their structures were confirmed. The ability of the catecholic nitriles and 6-substituted dopamine analogues to inhibit COMT was tested. The nitrile derivatives inhibited COMT most effectively, in agreement with our previous computational work. pKa values were used to further examine the factors involved with the inhibition and molecular docking studies were performed to support the ab initio and experimental work. The nitrile derivatives with a nitro substituent show the most promise as inhibitors, confirming that both the neutral tail and the electron withdrawing group are essential on this class of inhibitors.