Rasagiline, a suicide inhibitor of monoamine oxidases, binds reversibly to α-synuclein.

Rasagiline (N-propargyl-1-R-aminoindan) and selegiline (1-deprenyl) are MAO-B inhibitors which are used in the treatment of Parkinson's disease. The binding of rasagiline, selegiline, and their metabolites including 1-aminoindan, 2-aminoindan, and methamphetamine to α-synuclein was investigated by nanopore analysis and isothermal titration calorimetry. Blockade current histograms of α-synuclein alone give a peak at -86 pA which is due to translocation of the protein through the pore. In the presence of rasagiline and R-1-aminoindan, this peak shifts to about -80 pA. In the presence of selegiline and R-methamphetamine, the number of events at -86 pA is reduced and there is a higher proportion of bumping events at about -25 pA which are due to a more compact conformation. Rasagiline can also bind to sites in both the N- and C-terminal regions of α-synuclein. The binding constants of rasagiline and selegiline were estimated by isothermal titration calorimetry to be about 5 × 10(5) and <10(4) M(-1), respectively. A model is presented in which both rasagiline and R-1-aminoindan bind to α-synuclein, forming a loop structure which is less likely to aggregate or form fibrils. In contrast, selegiline binds and forms a more compact structure similar to that formed by methamphetamine.