FIASMA

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The term “ functional inhibitors of acid sphingomyelinase ” ( FIASMA for short ) is used to summarize a large number of pharmacological agents that inhibit the enzyme acid sphingomyelinase (ASM, EC  3.1.4.12 ). This enzyme is mainly located in the lysosome and breaks down sphingomyelin to ceramide and sphingosine , which in turn is metabolized to sphingosine-1-phosphate. These degradation products and thus also the inhibition of the enzyme itself influence the regulation of cell growth (proliferation) or cell death ( apoptosis ). Failure to regulate this balance can lead to serious clinical symptoms.

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

Mechanism of action of the FIASMAs

An indirect functional mechanism is assumed for the inhibitory effect of the FIASMAs on the ASM. FIASMAs lead to a detachment of the ASM from the inner lysosomal membrane with subsequent proteolytic degradation of the enzyme in the lysosomal lumen. The inhibitory effect of some pharmaceuticals on ASM has long been known, but was only systematically investigated later.

FIASMAs do not completely inhibit the ASM; a low residual activity of the enzyme ensures the necessary cellular metabolism. The clinical application of FIASMAs therefore does not lead to the picture of Niemann-Pick disease in which the activity of the ASM is completely absent due to a genetic defect.

Properties of the FIASMAs

FIASMAs are structurally heterogeneous, but have common physicochemical properties: All FIASMAs identified so far are lipophilic and weakly basic with at least one protonatable nitrogen atom; they therefore belong to the group of "cationic amphiphilic drugs". FIASMAs violate at least one of the Lipinski Rule-of-Five more often than non-FIASMAs. Nevertheless, FIASMAs are well absorbed into the body from the gastrointestinal tract and cross the blood-brain barrier .

Clinical pictures with increased formation of ceramide

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

Currently known FIASMAs

So far, the substances listed below have been identified as FIASMAs by cell culture experiments. H4 cells were used as reference cells ; the activity of the ASM was determined using a radioassay . In the absence of experimental data, the functionally inhibitory effect of a substance on the ASM can be calculated using a chemoinformatics model.

Individual evidence

  1. ↑ a b c J. Kornhuber, P. Tripal, M. Reichel, C. Mühle, C. Rhein, M. Muehlbacher, TW Groemer, E. Gulbins: Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. In: Cell Physiol Biochem . tape 26 , no. 1 , 2010, p. 9-20 , doi : 10.1159 / 000315101 , PMID 20502000 .
  2. ↑ M. Kölzer, N. Werth, K. Sandhoff K: Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine . In: FEBS Letters . tape 559 , no. 1 , 2004, p. 96-98 , doi : 10.1016 / S0014-5793 (04) 00033-X .
  3. ↑ N. Sakuragawa, M. Sakuragawa, T. Kuwabara, PG Pentchev, JA Barranger, RO Brady: Niemann-Pick disease experimental model: sphingomyelinase reduction induced by AY-9944. In: Science . 196, 1977, pp. 317-319. PMID 66749 .
  4. ↑ J. Kornhuber, P. Tripal, M. Reichel, L. Terfloth, S. Bleich, J. Wiltfang, E. Gulbins: Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model. In: J Med Chem. 51, 2008, pp. 219-237. PMID 18027916 .
  5. ↑ a b c d e f J. Kornhuber, M. Muehlbacher, S. Trapp, S. Pechmann, A. Friedl, M. Reichel, C. Mühle, L. Terfloth, T. Groemer; G. Spitzer, K. Liedl, E. Gulbins, P. Tripal: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . tape 6 , no. 8 , 2011, p. e23852 , doi : 10.1371 / journal.pone.0023852 .
  6. ↑ J. Kornhuber, A. Medlin, S. Bleich, V. Jendrossek, A. Henkel, J. Wiltfang, E. Gulbins: High activity of acid sphingomyelinase in major depression . In: J Neural Transm . tape 112 , no. 11 , 2010, p. 1583-1590 , doi : 10.1007 / s00702-005-0374-5 , PMID 16245071 .
  7. ^ V. Teichgräber, M. Ulrich, N. Endlich, JB Riethmüller-Wilker, CC de Oliveira-Munding, AM van Heeckeren, ML Barr, G. von Kürthy, KW Schmid, M. Weller, B. Tümmler, F. Lang , H. Grassme, G. Döring, E. Gulbins: Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. In: Nat Med . 14, 2008, pp. 382-391. PMID 18376404
  8. ↑ KA Becker, J. Riethmüller, A. Lüth, G. Döring, B. Kleuser, E. Gulbins: Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis. In: Am J Respir Cell Mol Biol. 42, 2010, pp. 716-724. PMID 19635928 .