Tedisamil

Tedisamil
Clinical data
ATC code	C01BD06 (WHO) ;
Identifiers
	IUPAC name 3,7-Bis(cyclopropylmethyl)-3,7-diazaspiro[bicyclo[3.3.1]nonane-9,1'-cyclopentane];
CAS Number	90961-53-8 ;
PubChem CID	65825;
IUPHAR/BPS	2567;
ChemSpider	28528215 ;
UNII	A5VAY2U3R8;
KEGG	D06652 ;
ChEMBL	ChEMBL113461 ;
CompTox Dashboard (EPA)	DTXSID30238334 ;
Chemical and physical data
Formula	C19H32N2
Molar mass	288.479 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C1CC2([C@H]3CN(C[C@@H]2CN(C3)CC4CC4)CC5CC5)CC1;
	InChI InChI=1S/C19H32N2/c1-2-8-19(7-1)17-11-20(9-15-3-4-15)12-18(19)14-21(13-17)10-16-5-6-16/h15-18H,1-14H2/t17-,18+ ; Key:CTIRHWCPXYGDGF-HDICACEKSA-N ;
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Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria.^[1] Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation.^[1] Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents.^[1] Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered.^[2] Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium.^[3]

Molecular problem

Arrhythmias are broadly defined as abnormal electrical activity in the heart and can affect both the atria and ventricles. Atrial arrhythmias are the most common type of arrhythmia with several subtypes currently described, including atrial fibrillation. In atrial fibrillation, there is continual quivering of the atria as contraction of the muscle is uncoordinated.^[4] Under normal conditions, an electrical impulse from the sinoatrial (SA) node is distributed rapidly throughout the atria causing coordinated excitement and inactivation of atrial muscle cell ion channels resulting in uniform contraction and relaxation of the muscle fibres.^[4] During fibrillation, other electrical signals overwhelm the SA node and ion channel excitement is no longer uniform throughout the atria.^[4] This results in inappropriate activation properties, further preventing uniform contraction and relaxation of the muscle.^[4] Subsequent action potentials from the SA node will not be able to uniformly excite the muscle as not all of the channels will be available to open as some will still be held in the inactivation phase.^[4] This results in disjointed contraction, or quivering, seen in the atrial muscle during fibrillation.

Mechanism of action

Tedisamil acts to restore normal electrical rhythm in the heart by prolonging the inactivation phase of the muscle. Both atrial and ventricular repolarization is lengthened by tedisamil by blocking multiple potassium channels including the transient outward (Ito), the adenosine triphosphate-dependent (IK-ATP), and the delayed rectifier potassium currents (IKr and IKs).^[5]^[6]^[7] Tedisamil action is dose dependent as currents are blocked longer and more effectively at higher concentrations.^[1] Tedisamil activity is greatest on Ito and acts by binding to the channel in its open configuration.^[5] This produces a blocked state and delays its inactivation.^[5] To restore normal function, tedisamil must unbind from the channel so that it can inactivate and eventually reopen.^[5] Similar mechanisms have been observed on the IKr and IKs currents.^[6] In both Ito and delayed rectifier channels, the tedisamil binding site appears to be internal as both binding and unbinding occur more effectively when tedisamil is applied inside the cell.^[6] Tedisamil also appears to provide specific, single channel blocking of IK-ATP at high concentrations.^[7] As the potassium channels are responsible for restoring the resting membrane potential during an action potential, lengthening their inactivation will stop the cycle of fibrillation by preventing muscle contraction until all ion channels are available to open. Regular use of tedisamil will prevent further fibrillation and restore normal electrical rhythm. Tedisamil’s antiarrythmic activity also appears to be supported by inhibiting sodium currents in cardiac muscle.^[5] However this is only observed at concentrations above 20μM, concentrations 20-fold higher than required for potassium channel blocks.^[5]

References

^ ^a ^b ^c ^d Hohnloser SH, Dorian P, Straub M, Beckmann K, Kowey P (July 2004). "Safety and efficacy of intravenously administered tedisamil for rapid conversion of recent-onset atrial fibrillation or atrial flutter". Journal of the American College of Cardiology. 44 (1): 99–104. doi:10.1016/j.jacc.2004.03.047. PMID 15234416.
^ Fox KM, Henderson JR, Kaski JC, Sachse A, Kuester L, Wonnacott S (February 2000). "Antianginal and anti-ischaemic efficacy of tedisamil, a potassium channel blocker". Heart. 83 (2): 167–71. doi:10.1136/heart.83.2.167. PMC 1729311. PMID 10648489.
^ Solvay Press Office. "Solvay Pharmaceuticals files Tedisamil, a new cardiometabolic product for the treatment of atrial fibrillation and atrial flutter". Retrieved February 1, 2011.
^ ^a ^b ^c ^d ^e Moe GK, Abildskov JA (July 1959). "Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge". American Heart Journal. 58 (1): 59–70. doi:10.1016/0002-8703(59)90274-1. PMID 13661062.
^ ^a ^b ^c ^d ^e ^f Wettwer E, Himmel HM, Amos GJ, Li Q, Metzger F, Ravens U (October 1998). "Mechanism of block by tedisamil of transient outward current in human ventricular subepicardial myocytes". British Journal of Pharmacology. 125 (4): 659–66. doi:10.1038/sj.bjp.0702110. PMC 1571017. PMID 9831899.
^ ^a ^b ^c Dukes ID, Cleemann L, Morad M (August 1990). "Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells". The Journal of Pharmacology and Experimental Therapeutics. 254 (2): 560–9. PMID 2384886.
^ ^a ^b Nemeth M, Varro A, Thormählen D, Papp J (1997). "Tedisamil is a potent blocker of ATP-sensitive potassium channels in cardiac muscle". Exp Clin Cardiol (2): 37–40.