FIASMA

Functional inhibitors of acid sphingomyelinase, or FIASMA,^[1] is a term which characterizes a large group of pharmacological compounds inhibiting the enzyme acid sphingomyelinase (ASM, EC 3.1.4.12). This enzyme is mainly located within the lysosome, where it cleaves sphingomyelin to ceramide and sphingosine, the latter of which is then phosphorylated to sphingosine-1-phosphate. These metabolites, and subsequent inhibition of the enzyme, influence the balance between cell death (apoptosis) and cell growth (proliferation). A lack of regulation of this sensitive equilibrium can lead to serious clinical consequences.

Mechanism of action of FIASMAs

FIASMAs inhibit the ASM via an indirect, functional mechanism. They insert into the inner leaf of the lysosomal membrane and subsequently cause membrane-associated enzymes, such as ASM, to detach.^[2] Upon detachment from the membrane, these enzymes are cleaved and degraded within lysosomes. Inhibition of ASM by certain drugs has been known about for a long time,^[3] but systematic studies which characterize the pharmacological group of FIASMAs are relatively recent.^[4] ASM is not completely inhibited by FIASMAs^[1] and a low residual activity remains, allowing sufficient metabolism for cellular survival to occur. Application of FIASMAs therefore do not result in a clinical condition like Niemann-Pick disease, where ASM-activity is completely lacking because of genetic mutations.

In contrast to FIASMAs, a screen of over 346,000 small molecules found only 20 that where direct inhibitors of acid sphingomyelinase. These 20 included amiodarone and etidronic acid.^[5]

Properties of FIASMAs

FIASMAs are structurally diverse, but have common physicochemical properties. All hitherto identified FIASMAs share a basic nitrogen atom^[6] and lipophilic part, which characterizes them as “cationic amphiphilic drugs”. Additionally, they also violate Lipinski's Rule of Five more often than non-FIASMAs.^[6] Still they are highly bioavailable and reabsorbed by the gastrointestinal tract. In general, they also show high blood–brain barrier permeability.^[6]

Ceramide and sphingomyelin are important in some clinical disease:

• In patients suffering with Major depressive disorder elevated ASM activity has been observed.^[7]
• In cystic fibrosis, accumulation of ceramide can be lowered using FIASMAs such as amitriptyline.^[8][9]

Known drugs acting as FIASMAs

Cell culture-based experiments identified the listed compounds as FIASMAs (antidepressants are in boldface). These experiments used the human cell line H4. The ASM activity was measured using a radiolabel assay.^[6] In case of absent experimental data a chemoinformatic prediction system has been proposed, which enables identification of FIASMAs based on molecular properties.^[6]

References

1. 1 2 Kornhuber J, Tripal P, Reichel M, Mühle C, Rhein C, Muehlbacher M, Groemer TW, Gulbins E (2010). "Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications.". Cell Physiol Biochem. 26 (1): 9–20. doi:10.1159/000315101. PMID 20502000. 
2. ↑ Kölzer M, Werth N, Sandhoff K (2004). "Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine". FEBS Letters. 559 (1): 96–98. doi:10.1016/S0014-5793(04)00033-X. 
3. ↑ Sakuragawa N, Sakuragawa M, Kuwabara T, Pentchev PG, Barranger JA, Brady RO (1977). "Niemann-Pick disease experimental model: sphingomyelinase reduction induced by AY-9944". Science. 196: 317–319. doi:10.1126/science.66749. PMID 66749. 
4. ↑ Kornhuber J, Tripal P, Reichel M, Terfloth L, Bleich S, Wiltfang J, Gulbins E (2008). "Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model". J Med Chem. 51: 219–237. doi:10.1021/jm070524a. PMID 18027916. 
5. ↑ Inhibitors of Secretory Acid Sphingomyelinase (S-ASM): qHTS http://pubchem.ncbi.nlm.nih.gov/assay/assay.cgi?aid=504937
6. 1 2 3 4 5 Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE. 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365. 
7. ↑ Kornhuber J, Medlin A, Bleich S, Jendrossek V, Henkel A, Wiltfang J, Gulbins E (2010). "High activity of acid sphingomyelinase in major depression". J Neural Transm. 112 (11): 1583–1590. doi:10.1007/s00702-005-0374-5. PMID 16245071. 
8. ↑ Teichgräber V, Ulrich M, Endlich N, Riethmüller Wilker JB, de Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kürthy G, Schmid KW, et al. (2008). "Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis". Nat Med. 14: 382–391. doi:10.1038/nm1748. PMID 18376404. 
9. ↑ Becker KA, Riethmüller J, Lüth A, Döring G, Kleuser B, Gulbins E (2010). "Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis". Am J Respir Cell Mol Biol. 42: 716–724. doi:10.1165/rcmb.2009-0174OC. PMID 19635928.