Design, synthesis and analysis of novel dopaminergic and catecholic ligands as inhibitors of catechol-O-methyltransferase

Abstract

L-DOPA, a dopamine precursor, is commonly used as a pharmacological treatment for patients with conditions such as Parkinson’s disease. Therapeutic L-DOPA, as well as the dopamine derived from L-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). The targeted inhibition of the COMT enzyme prolongs the effectiveness of L-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Two classes of novel derivatives have been proposed and analyzed through in silico models that apply density functional theory and Møller–Plesset perturbation theory methods. The inhibitory capacities of the ligands were determined by the relative binding affinity of each ligand in the active site model. Three active site models were analyzed in order to compare computational methods and simulate physiological conditions. The lipophilicity of the proposed ligands was determined computationally as well. Following the completion of the computational analysis, several of the proposed catecholic ligands, namely 3,4-dihydroxybenzonitrile, 2-(3,4-dihydroxyphenyl)acetonitrile and 3-(3,4-dihydroxyphenyl)propanenitrile, were synthesized and analyzed experimentally to confirm structure and purity and to determine lipophilicity.