The structure electro-activity relationship (SeAR) of xanthine and uric acid metabolites and related structures to caffeine were studied (Table ). SeAR is a promising method to explore the findings of cyclic voltammetry (CV) studies as a predictive tool for determining where oxidative structure modification may occur on a skeletal framework. Based on the oxidation potential information derived from Table (and supporting information: correlation between log10 peak potential and log10 peak current versus scan rate), the following trends based on matched-molecular-pair (MMP) analysis were identified. Desmethylating the N7-R'' position from methyl in 1 to hydrogen in 4 resulted in limited change (1.23 V vs 1.21 V). Taken together, these findings suggest the N1 and N7 positions in caffeine had no significant effect on oxidation potential, implying the R groups attached here on caffeine are less labile to oxidation than the N3 position, at least for the initial electrooxidation step and as observed with the major metabolite paraxanthine with CYP1A2. Furthermore, connections between the electrochemical behavior observed in these caffeine analogues and metabolites were compared to their half-life in vitro and in vivo (SI: Relationship between observed oxidation potential and half-life).