We then synthesized various analogues of MP36 (Figure ). MP47 and MP48 were created using intramolecular amination or acylation chemistry to close the ring. This is the equivalent of opening the pyridinium ring and deleting the positive charge. MP49 and MP50 were created by closing the ring through thioether bond formation and thus lack any trace of the IP + moiety. The passive permeabilities of these four molecules were assessed using PAMPA. As shown in Figure (yellow dots), each of these molecules displayed a passive permeability between 10-and 100-fold poorer than the IP + -containing MP36. This comparative assessment shows that the IP + unit has a major positive effect on the passive membrane permeability of the MPs.