Repositioning of dantrolene for Alzheimer’s disease: new and old biological activities towards AD-related targets.

Dantrolene is a life-saving drug used for the treatment of malignant hyperthermia, a pharmacogenetic disease triggered by many anesthetics used in clinical surgery. It acts by inhibiting ryanodine receptors (RyRs), which are responsible for calcium mobilization in striatal muscles and brain. This feature has suggested a possible use of dantrolene in AD, as demonstrated by several reports in animal models of the disease.1 Recently, we presented previously undisclosed activities of dantrolene (Figure 1), namely the inhibition of monoamine oxidase B (MAO B), acetylcholinesterase (AChE), and beta amyloid (Abeta) aggregation, and the activation of the carrier of L-acylcarnitine (CACT), as concomitant biological features responsible for neuroprotection.2 To overcome the low aqueous solubility of dantrolene, either as free base or sodium salt, we also dealt with the synthesis of selected structural congeners, with the aim of confirming their multitarget profile while improving the solubility. The newly synthesized compounds retained good AChE/MAO B inhibitory activity, with moderate to good activation of CACT. Results from ongoing studies will be presented and discussed.