FIASMA

The term "functional inhibitors of acid sphingomyelinase " (short FIASMA ) summarizes put together a variety of pharmacological agents that inhibit the enzyme acid sphingomyelinase (ASM, EC 3.1.4.12 ). This enzyme is found mainly in the lysosome and builds sphingomyelin to ceramide and sphingosine from which is in turn metabolized to sphingosine-1- phosphate. These degradation products, and thus the inhibition of the enzyme itself affect the regulation of cell growth (proliferation ) and cell death ( apoptosis). Dysregulation of this balance can lead to serious clinical conditions.

The acronym " FIASMA " for this group of substances derived from the English term Functional Inhibitor of Acid sphingomyelinase.

Mechanism of action of FIASMAs

For the inhibitory effect of the ASM FIASMAs an indirect, functional mechanism, it is assumed. FIASMAs lead to a separation of the ASM from the inner lysosomal membrane with subsequent proteolytic degradation of the enzyme in the lysosomal lumen. The inhibitory effect of some drugs on the ASM has long been known, but was later systematically studied.

FIASMAs inhibit ASM is not complete; a small residual activity of the enzyme ensures the necessary cellular metabolism. The clinical application of FIASMAs therefore does not produce the image of Niemann -Pick disease, wherein the activity of the ASM by a genetic defect is completely missing.

Properties of FIASMAs

FIASMAs are structurally heterogeneous, but share common physicochemical properties: All previously identified FIASMAs are lipophilic and weakly basic with at least one protonated nitrogen atom; therefore they belong to the group of " cationic amphiphilic drugs". FIASMAs frequently violate at least one of Lipinski Rule -of -Five rules as non- FIASMAs. Nevertheless FIASMAs be well absorbed from the gastrointestinal tract into the body and pass through the blood -brain barrier.

Diseases with increased formation of ceramide

• "Major depression": In patients with "major depression" increased activity of ASM was found in a pilot study. FIASMAs could normalize the increased activity in depression of the ASM again.
• Cystic fibrosis or cystic fibrosis: which occurs with this disease accumulation of ceramide can be normalized by FIASMAs such as amitriptyline.

Currently known FIASMAs

Been standing by cell culture experiments below have been identified as substances FIASMAs. As reference cells H4 cells were used; ASM activity was determined using a radio- assay. Absence of experimental data, the functional inhibitory effect of a substance on the ASM can be calculated with a chemo informatics model.