A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves A[beta]^sub 25-35^-impaired mouse cognitive function

Rationale The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy. Objectives We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-A[beta]^sub 25-35^-injected mice, and the potential mechanisms. Methods AChE activity assay, intracellular Ca^sup 2+^ content and calcium currents measurement, and A[beta]^sub 25-35^-induced cellular death determine were performed for validation of designed targets and neuroprotection of SCR-1693. Mice were orally administrated with SCR-1693 once daily after an A[beta]^sub 25-35^ injection. The Morris water maze and Y-maze test, and hippocampal protein detection were conducted on days 5-10, day 11, and day 8. The pyramidal neuron number, hippocampal AChE activity, and synaptic transmission were measured on day 12. Results SCR-1693 acted as a selective, reversible, and noncompetitive inhibitor of AChE, and a nonselective voltage-gated calcium channel blocker. SCR-1693 also inhibited the increase of AChE activity in the mouse hippocampus. SCR-1693 was more effective than donepezil and memantine in preventing A[beta]^sub 25-35^-induced long-term and short-term memory impairment, maintaining the basal transmission of Schaffer collateral-CA1 synapses, and sustaining LTP in mouse hippocampus. SCR-1693 attenuated A[beta]^sub 25-35^-induced death of SH-SY5Y cell and the loss of hippocampal pyramidal neurons, and regulated A[beta]^sub 25-35^-induced signal cascade in neurons. Conclusions All these findings indicated that SCR-1693, as a double-target-direction agent, is a considerable candidate for AD therapy.