JTV-519

Last updated
JTV-519
JTV-519.svg
Names
Preferred IUPAC name
3-(4-Benzylpiperidin-1-yl)-1-(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)propan-1-one
Other names
K201
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.236.521 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • O=C(N1CCSC(C=CC(OC)=C2)=C2C1)CCN(CC3)CCC3CC4=CC=CC=C4
Properties
C25H32N2O2S
Molar mass 424.60 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

JTV-519 (K201) is a 1,4-benzothiazepine derivative that interacts with many cellular targets. [1] It has many structural similarities to diltiazem, a Ca2+ channel blocker used for treatment of hypertension, angina pectoris and some types of arrhythmias. [2] JTV-519 acts in the sarcoplasmic reticulum (SR) of cardiac myocytes by binding to and stabilizing the ryanodine receptor (RyR2) in its closed state. [3] [4] It can be used in the treatment of cardiac arrhythmias, heart failure, catecholaminergic polymorphic ventricular tachycardia (CPVT) and store overload-induced Ca2+ release (SOICR). [2] [3] [4] Currently, this drug has only been tested on animals and its side effects are still unknown. [5] As research continues, some studies have also found a dose-dependent response; where there is no improvement seen in failing hearts at 0.3 μM and a decline in response at 1 μM. [4]

Contents

Treatment with JTV-519 involves stabilization of RyR2 in its closed state, decreasing its open probability during diastole and inhibiting a Ca2+ leak into the cell's cytosol. [3] [4] By decreasing the intracellular Ca2+ leak, it is able to prevent Ca2+ sparks or increases in the resting membrane potential, which can lead to spontaneous depolarization (cardiac arrhythmias), and eventually heart failure, due to the unsynchronized contraction of the atrial and ventricular compartments of the heart. [2] [3] [4] When Ca2+ sparks occur from the SR, the increase in intracellular Ca2+ contributes to the rising membrane potential which leads to the irregular heart beat associated to cardiac arrhythmias. [3] It can also prevent SOICR in the same manner; preventing opening of the channel due to the increase of Ca2+ inside the SR levels beyond its threshold. [2]

Molecular problem

In the closed state, N-terminal and central domains come into close contact interacting to cause a “zipping” of domains. This leads to conformational constraints that stabilize the channel and maintain the closed state. [1] Most RyR2 mutations are clustered into three regions of the channel, all affecting the same domains that interact to stabilize the channel. [1] Any of these mutations can lead to “unzipping” of the domains and a decrease in the energy barrier required for opening the channel (increasing its open probability). [1] This channel “unzipping” allows for an increase in protein kinase A phosphorylation and calstabin2 dissociation. Phosphorylation of RyR2 increases the channel's response to Ca2+, which usually binds the RyR2 to open it. [1] If the channel become phosphorylated, this can lead to an increase in Ca2+ sparks due to an increase in Ca2+ sensitivity.

Some researchers believe that the depletion of calstabin2 from the RyR2 causes the calcium leak. [3] The depletion of calstabin2 can occur in both heart failure and CPVT. [3] Calstabin2 is a protein that stabilizes RyR2 in its closed state, preventing Ca2+ leakage during diastole. When calstabin2 is lost, the interdomain interactions of RyR2 become loose, allowing the Ca2+ leak. [3] However, the role of calstabin2 has been controversial, as some studies have found it necessary for the effect of JTV-519, [3] whereas others have found the drug functions without the stabilizing protein. [2]

Molecular mechanism

JTV-519 seems to restore the stable conformation of RyR2 during the closed state. [1] [4] It is still controversial whether or not calstabin2 is necessary for this process, however, many studies believe that JTV-519 can act directly on the channel and by binding, prevents conformational changes. [2] This stabilization of the channel decreases its open probability resulting in fewer leaks of Ca2+ into the cytosol and fewer Ca2+ sparks to occur. [3] [4] Researchers who believe that calstabin2 is necessary for JTV-519 effect, found that this drug may function by inducing the binding of calstabin2 back to the channel or increasing calstabin2's affinity for the RyR2 and thus increasing its stability. [2] [3]

Related Research Articles

Sarcoplasmic reticulum Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger; see calcium in biology for more details). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.

Flecainide Antiarrhythmic medication used to prevent and treat tachyarrhythmias

Flecainide is a medication used to prevent and treat abnormally fast heart rates. This includes ventricular and supraventricular tachycardias. Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments. Its use does not decrease a person's risk of death. It is taken by mouth or injection into a vein.

Muscle contraction Activation of tension-generating sites in muscle

Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such as when holding a heavy book or a dumbbell at the same position. The termination of muscle contraction is followed by muscle relaxation, which is a return of the muscle fibers to their low tension-generating state.

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.

Calsequestrin

Calsequestrin is a calcium-binding protein that acts as a calcium buffer within the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also helps the sarcoplasmic reticulum store an extraordinarily high amount of calcium ions. Each molecule of calsequestrin can bind 18 to 50 Ca2+ ions. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface. Two forms of calsequestrin have been identified. The cardiac form Calsequestrin-2 (CASQ2) is present in cardiac and slow skeletal muscle and the fast skeletal form Calsequestrin-1(CASQ1) is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation. When calcium binds there is a structural change whereby the alpha-helical content of the protein increases from 3 to 11%. Both forms of calsequestrin are phosphorylated by casein kinase 2, but the cardiac form is phosphorylated more rapidly and to a higher degree. Calsequestrin is also secreted in the gut where it deprives bacteria of calcium ions..

Catecholaminergic polymorphic ventricular tachycardia Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

A calcium spark is the microscopic release of calcium (Ca2+) from a store known as the sarcoplasmic reticulum (SR), located within muscle cells. This release occurs through an ion channel within the membrane of the SR, known as a ryanodine receptor (RyR), which opens upon activation. This process is important as it helps to maintain Ca2+ concentration within the cell. It also initiates muscle contraction in skeletal and cardiac muscles and muscle relaxation in smooth muscles. Ca2+ sparks are important in physiology as they show how Ca2+ can be used at a subcellular level, to signal both local changes, known as local control, as well as whole cell changes.

Ryanodine receptor 2

Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the RYR2 gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

FKBP1B

Peptidyl-prolyl cis-trans isomerase FKBP1B is an enzyme that in humans is encoded by the FKBP1B gene.

Triadin Protein-coding gene in the species Homo sapiens

Triadin, also known as TRDN, is a human gene associated with the release of calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release. Triadin is a multiprotein family, arising from different processing of the TRDN gene on chromosome 6. It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section and it forms a quaternary complex with the cardiac ryanodine receptor (RYR2), calsequestrin (CASQ2) and junctin proteins. The luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca2+ receptors. Triadin is also able to sense luminal Ca2+ concentrations by mediating interactions between RYR2 and CASQ2. Triadin has several different forms; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle.

Ryanodine receptor 1

Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle. In humans, it is encoded by the RYR1 gene.

Ankyrin-B, also known as Ankyrin-2, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-B is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-B plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ankyrin-B cause a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-B expression levels are observed in human heart failure.

Imperatoxin I (IpTx) is a peptide toxin derived from the venom of the African scorpion Pandinus imperator.

Celivarone Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

Mydicar is a genetically targeted enzyme replacement therapy being studied for use in patients with severe heart failure. It is designed to increase the level of SERCA2a, a sarcoplasmic endoplasmic reticulum calcium (Ca2+) ATPase found in the membrane of the sarcoplasmic reticulum (SR). The SERCA2a gene is delivered to the heart via an adeno-associated viral vector. Using the α-myosin heavy chain gene promoter in the cardiac muscle cells, also called cardiomyocytes, Mydicar is able to direct the gene expression only to the heart muscle. Mydicar is being tested in a phase 2 study, in which has been compared to a placebo in 39 advanced heart failure patients. Thus far, patients treated with Mydicar have shown a 52% reduction in the risk of worsening heart failure compared to patients treated with the placebo.

Calcium buffering describes the processes which help stabilise the concentration of free calcium ions within cells, in a similar manner to how pH buffers maintain a stable concentration of hydrogen ions. The majority of calcium ions within the cell are bound to intracellular proteins, leaving a minority freely dissociated. When calcium is added to or removed from the cytoplasm by transport across the cell membrane or sarcoplasmic reticulum, calcium buffers minimise the effect on changes in cytoplasmic free calcium concentration by binding calcium to or releasing calcium from intracellular proteins. As a result, 99% of the calcium added to the cytosol of a cardiomyocyte during each cardiac cycle becomes bound to calcium buffers, creating a relatively small change in free calcium.

The ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family includes Ryanodine receptors and Inositol trisphosphate receptors. Members of this family are large proteins, some exceeding 5000 amino acyl residues in length. This family belongs to the Voltage-gated ion channel (VIC) superfamily. Ry receptors occur primarily in muscle cell sarcoplasmic reticular (SR) membranes, and IP3 receptors occur primarily in brain cell endoplasmic reticular (ER) membranes where they effect release of Ca2+ into the cytoplasm upon activation (opening) of the channel. They are redox sensors, possibly providing a partial explanation for how they control cytoplasmic Ca2+. Ry receptors have been identified in heart mitochondria where they provide the main pathway for Ca2+ entry. Sun et al. (2011) have demonstrated oxygen-coupled redox regulation of the skeletal muscle ryanodine receptor-Ca2+ release channel (RyR1;TC# 1.A.3.1.2) by NADPH oxidase 4.

Cardiac excitation-contraction coupling (CardiacEC coupling) describes the series of events, from the production of an electrical impulse (action potential) to the contraction of muscles in the heart. This process is of vital importance as it allows for the heart to beat in a controlled manner, without the need for conscious input. EC coupling results in the sequential contraction of the heart muscles that allows blood to be pumped, first to the lungs (pulmonary circulation) and then around the rest of the body (systemic circulation) at a rate between 60 and 100 beats every minute, when the body is at rest. This rate can be altered, however, by nerves that work to either increase heart rate (sympathetic nerves) or decrease it (parasympathetic nerves), as the body's oxygen demands change. Ultimately, muscle contraction revolves around a charged atom (ion), calcium (Ca2+), which is responsible for converting the electrical energy of the action potential into mechanical energy (contraction) of the muscle. This is achieved in a region of the muscle cell, called the transverse-tubule during a process known as calcium induced calcium release.

Intrepicalcin (ViCaTx1) is a short peptide toxin found in the venom of scorpion Vaejovis intrepidus. It is one of a group of short, basic peptides called calcins, which bind to ryanodine receptors (RyRs) and thereby trigger calcium release from the sarcoplasmic reticulum.

References

  1. 1 2 3 4 5 6 Oda, T; Yano, M; Yamamoto, T; Tokuhisa, T; Okuda, S; Doi, M; Ohkusa, T; Ikeda, Y; et al. (2005). "Defective regulation of interdomain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure". Circulation. 111 (25): 3400–10. doi: 10.1161/CIRCULATIONAHA.104.507921 . PMID   15967847.
  2. 1 2 3 4 5 6 7 Hunt, DJ; Jones, PP; Wang, R; Chen, W; Bolstad, J; Chen, K; Shimoni, Y; Chen, SR (2007). "K201 (JTV519) suppresses spontaneous Ca2+ release and 3Hryanodine binding to RyR2 irrespective of FKBP12.6 association". The Biochemical Journal. 404 (3): 431–8. doi:10.1042/BJ20070135. PMC   1896290 . PMID   17313373.
  3. 1 2 3 4 5 6 7 8 9 10 11 Wehrens, XH; Lehnart, SE; Reiken, SR; Deng, SX; Vest, JA; Cervantes, D; Coromilas, J; Landry, DW; Marks, AR (2004). "Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2". Science. 304 (5668): 292–6. doi:10.1126/science.1094301. PMID   15073377. S2CID   41980576.
  4. 1 2 3 4 5 6 7 Toischer, K; Lehnart, SE; Tenderich, G; Milting, H; Körfer, R; Schmitto, JD; Schöndube, FA; Kaneko, N; et al. (2010). "K201 improves aspects of the contractile performance of human failing myocardium via reduction in Ca2+ leak from the sarcoplasmic reticulum". Basic Research in Cardiology. 105 (2): 279–87. doi:10.1007/s00395-009-0057-8. PMC   2807967 . PMID   19718543.
  5. ↑ Viswanathan, MN; Page, RL (2009). "Pharmacological therapy for atrial fibrillation: Current options and new agents". Expert Opinion on Investigational Drugs. 18 (4): 417–31. doi:10.1517/13543780902773410. PMID   19278302. S2CID   71155277.
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