Rasagiline derivatives combined with histamine H3 receptor properties.

The irreversible monoamine oxidase B (MAO B) inhibitor rasagiline has been described with multiple disease modifying effects in vitro on models of Parkinson's disease. The combination of this established drug to recently developed histamine H3 receptor (H3R) antagonist elements gives new impetus to the design of multitargeting ligands. Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 1 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC50 = 256 nM; hH3R Ki = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H1, H4, dopamine D2, D3 receptors or acetyl-/butyrylcholinesterases.