Functional inhibitors of acid sphingomyelinase, or FIASMA, is a large group of pharmacological compounds inhibiting the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

acid sphingomyelinase (ASM, EC 3.1.4.12). This enzyme is mainly located within the

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...

, where it cleaves

sphingomyelin Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosp ...

ceramide Ceramides are a family of waxy lipid molecules. A ceramide is composed of N-acetyl sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of eukaryotic cells, since they are component lipids that make ...

and

sphingosine Sphingosine (2-amino-4-trans-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain, which forms a primary part of sphingolipids, a class of cell membrane lipids that include sphingomyelin, an important phos ...

, the latter of which is then phosphorylated to

sphingosine-1-phosphate Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcoho ...

. 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. The acronym "FIASMA" was introduced by Kornhuber and coworkers; it is derived from the term ''Functional Inhibitor of Acid SphingoMyelinAse''.

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. 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, but systematic studies which characterize the pharmacological group of FIASMAs are relatively recent. ASM is not completely inhibited by FIASMAs 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 were direct inhibitors of acid sphingomyelinase. These 20 included

amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibril ...

and

etidronic acid Etidronic acid, also known as etidronate, is a non-nitrogenous bisphosphonate used as a medication, detergent, water treatment, and cosmetic. It was patented in 1966 and approved for medical use in 1977. Use Medical Etidronic acid is a bisph ...

Properties of FIASMAs

FIASMAs are structurally diverse, but have common physicochemical properties. All FIASMAs identified so far share a basic nitrogen atom and

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

part, which characterizes them as “cationic amphiphilic drugs”. Additionally, they also violate

Lipinski's Rule of Five Lipinski's rule of five, also known as Pfizer's rule of five or simply the rule of five (RO5), is a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical pro ...

more often than non-FIASMAs. Still, they are highly bioavailable and reabsorbed by the gastrointestinal tract. In general, they also show high blood–brain barrier permeability. Ceramide and sphingomyelin have clinical relevance: * In patients with

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

, elevated ASM activity has been observed. * In cystic fibrosis, accumulation of ceramide can be lowered using FIASMAs such as

amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

Known drugs acting as FIASMAs

Cell culture-based experiments identified the listed compounds as FIASMAs (

antidepressants Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

are in boldface). These experiments used the human cell line H4. The ASM activity was measured using a radiolabel assay. In case of absent experimental data a chemoinformatic prediction system has been proposed, which enables identification of FIASMAs based on molecular properties. {{columns-list, colwidth=18em, *

Alverine Alverine is a drug used for functional gastrointestinal disorders. Alverine is a smooth muscle relaxant. Smooth muscle is a type of muscle that is not under voluntary control; it is the muscle present in places such as the gut and uterus. A ...

Amiodarone Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibril ...

Amitriptyline Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat cyclic vomiting syndrome (CVS), major depressive disorder and a variety of pain syndromes from neuropathic pain to fibromyalgi ...

Amlodipine Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure and coronary artery disease. It is taken by mouth. Common side effects include swelling, feeling tired, ...

Aprindine Aprindine is a Class 1b antiarrhythmic agent Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, s ...

Astemizole Astemizole (marketed under the brand name Hismanal, developmental code R43512) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It was withdrawn from the m ...

* AY-9944 *

Benzatropine Benzatropine ( INN), known as benztropine in the United States and Japan, is a medication used to treat movement disorders like parkinsonism and dystonia, as well as extrapyramidal side effects of antipsychotics, including akathisia. It is not u ...

Bepridil Bepridil (trade name Vascor) is an diamine calcium channel blocker once used to treat angina pectoris. It is no longer sold in the United States. It is nonselective. It has been discussed as a possible option in the treatment of atrial fibrilla ...

Biperiden Biperiden, sold under the brand name Akineton among others, is a medication used to treat Parkinson disease and certain drug-induced movement disorders. It is not recommended for tardive dyskinesias. It is taken by mouth, injection into a vein, ...

* Camylofin * Carvedilol * Cepharanthine *

Chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar di ...

* Chlorprothixene *

Cinnarizine Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. It is prescribed for nausea and vomiting due to motion sickness or other sources such as chemotherapy, vertigo, or Ménière's disease. Cinnariz ...

* Clemastine *

Clofazimine Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...

* Clomiphene *

Clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used for the treatment of obsessive–compulsive disorder, panic disorder, major depressive disorder, and chronic pain. It may increase th ...

Cloperastine Cloperastine (INN) or cloperastin, in the forms of cloperastine hydrochloride ( JAN) (brand names Hustazol, Nitossil, Seki) and cloperastine fendizoate (or hybenzoate), is an antitussive and antihistamine that is marketed as a cough suppressant ...

* Conessine * Cyclobenzaprine *

Cyproheptadine Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine, first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties. It was patented in 1959 an ...

Desipramine Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...

* Desloratadine *

Dicycloverine Dicycloverine, also known as dicyclomine, sold under the brand name Bentyl in the US, is a medication that is used to treat spasms of the intestines such as occur in irritable bowel syndrome. It is taken by mouth or by injection into a muscle. ...

Dicyclomine Dicycloverine, also known as dicyclomine, sold under the brand name Bentyl in the US, is a medication that is used to treat spasms of the intestines such as occur in irritable bowel syndrome. It is taken by mouth or by injection into a muscl ...

Dilazep Dilazep is a vasodilator that acts as an adenosine reuptake inhibitor. It is used for the treatment of cardiopathy and renal disorders. Synthesis The reaction of bis-(3-hydroxypropyl)-ethylene diamine (1) with 1-Bromo-3-chloropropane (2) gives ...

* Dimebon *

Doxepin Doxepin is a medication falling in the tricyclic antidepressant (TCA) class used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For label updates seFDA index page for NDA 022036/ref> For hives it is a less ...

Drofenine Drofenine is an antimuscarinic antispasmodic drug used for relaxing smooth muscle, thereby treating conditions, such as: dysmenorrhea, and pain in the gastrointestinal tract, biliary passages, and urogenital tract. Drofenine is assumed to work b ...

Emetine Emetine is a drug used as both an anti-protozoal and to induce vomiting. It is produced from the ipecac root. It takes its name from its emetic properties. Early preparations Mechanism of action of emetine was studied by François Magendie durin ...

* Fendiline *

Flunarizine Flunarizine, sold under the brand name Sibelium among others, is a drug classified as a calcium antagonist which is used for various indications. It is not available by prescription in the United States or Japan. The drug was discovered at Janss ...

* Fluoxetine *

Flupentixol Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. It was introduced in 1965 by Lundbeck. In addition to single drug pre ...

Fluphenazine Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. It is used in the treatment of chronic psychoses such as schizophrenia, and appears to be about equal in effectiveness to low-pote ...

Fluvoxamine Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...

Hydroxyzine Hydroxyzine, sold under the brand names Atarax, Vistaril and others, is an antihistamine medication. It is used in the treatment of itchiness, insomnia, anxiety, and nausea, including that due to motion sickness. It is used either by mouth or ...

* Imipramine *

Lofepramine Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression. The TCAs are so named as they share the common property of having three rings in their che ...

* Loperamid * Loratadin *

Maprotiline Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary am ...

* Mebeverine * Mebhydrolin *

Mepacrine Mepacrine, also called quinacrine or by the trade name Atabrine, is a medication with several uses. It is related to chloroquine and mefloquine. Although formerly available from compounding pharmacies, as of August 2020 it is unavailable in th ...

* Mibefradil * Norfluoxetine *

Nortriptyline Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is used for: neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. As with many a ...

Paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...

Penfluridol Penfluridol (Semap, Micefal, Longoperidol) is a highly potent, first generation diphenylbutylpiperidine antipsychotic. It was discovered at Janssen Pharmaceutica in 1968. Related to other diphenylbutylpiperidine antipsychotics, pimozide and flus ...

Perhexiline Perhexiline (Pexsig) is a prophylactic antianginal agent used primarily in Australia and New Zealand. Perhexiline is thought to act by inhibiting mitochondrial carnitine palmitoyltransferase-1. This shifts myocardial metabolism from fatty acid ...

Perphenazine Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades. Perphenazine is roughly ten times as pote ...

Pimethixene Pimethixene is an antihistamine and anticholinergic of the thioxanthene chemical class originally developed to treat hyperactivity, anxiety, sleep disorders, and allergy. It is also used for anesthesia and as a bronchodilator (to dilate the bronc ...

Pimozide Pimozide (sold under the brand name Orap) is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis ...

* Profenamine * Promazine *

Promethazine Promethazine is a first-generation antihistamine, antipsychotic, sedative, and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating people ...

* Protriptyline * Sertindole *

Sertraline Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...

Solasodine Solasodine is a poisonous alkaloid chemical compound that occurs in plants of the family Solanaceae such as potatoes and tomatoes. Solasonine and solamargine are glycoalkaloid derivatives of solasodine. Solasodine is teratogenic to hamster fetus ...

* Suloctidil *

Tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...

Terfenadine Terfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel (now Sanofi-Aventis) and was marketed under various brand names, including Seldane in the United States, Tr ...

Thioridazine Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwid ...

Tomatidine Tomatidine is an anabolic chemical compound that prevents muscle wasting. It is naturally found in leaves of tomatoes and green tomatoes. Chemically, it is the aglycone of tomatine. It has been shown to have multiple health benefits. Tomatidine i ...

* Trifluoperazin * Triflupromazine * Trimipramine * Zolantidine

References

Enzyme inhibitors