Mechanistic insights on the antioxidant activity of selected neurotransmitters

Antioxidant activity of neurotransmitters such as dopamine, serotonin, and octopamine are studied employing density functional theory at the M062X/6-311+G∗∗ level. The hydroperoxyl radical scavenging activity of these molecules is evaluated based on thermodynamic and kinetic calculations in the gas phase as well as in solvents that mimic physiological environments. The HAT mechanism is predicted to be favored in the gas phase, whereas the SPLET mechanism is preferred in water as well as in the lipid medium. Antioxidant activity of these molecules is attributed to the presence of phenolic OH groups. Dopamine is found to be the most active antioxidant in gas as well as polar medium, whereas Serotonin exhibited higher reactivity in the lipid medium. It is identified that the nature of the environment influences the antioxidant activity of these molecules. H-bonding interaction involving the vicinal OH group of the phenoxide radical is identified to be crucial towards stabilizing the radical generated from the D2 site of dopamine, making it the most reactive site of radical attack as per the HAT mechanism. Kinetic calculations of the HAT mechanism suggest that the D2 site of dopamine has the highest rate constant both in the gas phase (1.32 × 10⁶ L mol^-1 s^-1) as well as in aqueous medium (9.11 × 10³ L mol^-1 s^-1), whereas the S1 site of serotonin is predicted to be the most feasible site of attack in the lipid medium (2.15 × 10⁵ L mol^-1 s^-1). Octopamine is found to be the least reactant molecule among the three.