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Oxidative stress is known to be the main factor involved in neurodegeneration and its aggravation is often associated to pro-oxidant molecules crossing blood-brain barrier. In this context, the investigation of the redox behavior of central acting drugs might provide relevant data to describe either if these compounds could end up promoting the genesis of reactive oxygen species (ROS), or scavenge them. Among the most commercialized central acting drugs in the marked is tramadol (TRA), whose biological activities are achieved by interaction with several bodily receptors such as μ-opioid receptor. The chronic intake of TRA is reported to enhance oxidative stress and promote neurodegeneration, what henceforth suggests this compound to exert pro-oxidant activities. This work therefore targeted the investigation of TRA redox behavior through electrochemical and quantum chemistry approaches (i.e. voltametry and Extended Huckel Method – EHM, respectively) in order to shed light on the thermodynamic and kinetic features associated to TRA pro-oxidant nature. Quantum chemistry results by EHM showcased that the energy gap between the highest occupied molecular orbitals (HOMO-n) and the lowest unoccupied molecular orbital (LUMO-n) as well as their displacements in the rendered model suggests that TRA tertiary amine and the aromatic ring moieties would be the most likely regions wherein oxidation and reduction would take place, respectively. Considering that previous outreaches showcase the correlation of HOMO-n and LUMO-n to various oxidation and reduction states in molecules, HOMO-0 therefore suggests the most thermodynamically feasible site for the first TRA oxidation (i.e. tertiary amine), whereas HOMO-1 and LUMO-0 suggests that the second oxidation and first reduction would most likely take place at TRA aromatic ring. The electrochemical results showcased that TRA presents two anodic peaks (1a and 2a) at electric potentials of +0.1 and +0.8 V, which are associated to the oxidation of electroactive moieties in TRA molecule. A cathodic process (1c) was also detected and it was seemingly associated to anodic peak 1a, hence suggesting a quasi-reversible reaction. Through these findings, an electro-oxidation pathway was proposed, depicting the oxidation of the tertiary amine, followed by demethylation and the formation of a catechol-quinone redox system, which was corroborated by the findings of other authors. The low kinetic associated to peaks 1a and 1c suggests that few molecules undergo this process. In this sense, considering that endogenous antioxidants are known to reduce ROS at electric potentials below +0.5 V due to favorable thermodynamic, TRA seemingly does not showcase noteworthy antioxidant potential. The second oxidation peak (2a) was seemingly irreversible, and taking into account that oxidation reactions are known to render highly energetic compounds (i.e. ROS), the voltammetric profile of TRA suggests pro-oxidant properties. Therefore, this work showcased how electrochemistry and EHM can be associated to readily investigate the redox behavior of central acting drugs under low cost, and shed light on their pro-oxidant or antioxidant potential.

Redox Behavior of Central-Acting Opioid Tramadol and Its Possible Role in Oxidative Stress