Membrane transporters play a significant role in the transport of many endogenous and exogenous compounds. Here we demonstrate that inclusion of a biguanide functionality can improve the compound uptake mediated by organic cation transporters 1 and 2 (OCT1 and OCT2). We synthesized 18 pairs of potential OCT substrates with either an amino compound or a biguanide group; and assessed their uptake in cells overexpressing human OCT1 or OCT2. Our results showed that the presence of the biguanide functionality significantly improved OCT1 and OCT2-mediated update. The biguanides also inhibited the uptake of prototypical substrates of both transporters, 1-methyl-4-phenylpyridinium (MPP+) and metformin. In addition, we found that molecular weight, molecular volume, LogD (pH 7.4) and accessible surface area were key determinants of OCT2 substrates, but none of these parameters was a significant factor for OCT1. Moreover, the inhibition of MPP+ uptake correlated linearly with that of metformin uptake for the tested biguanides in both cell lines. OCT1-mediated MPP+ and metformin inhibition was negatively correlated with biguanide molecular weight, molecular volume, and accessible surface area.

Incorporation of a biguanide scaffold enhances uptake by organic cation transporters (OCT) 1 and 2

254th National Meeting (2017)

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