Effects of Novel Synthesized Pyridothiazines on Various Guinea Pig Heart Muscle Preparations(Pharmacology)

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概要

• 論文の詳細を見る

• Calcium channel blockers have become important tools in the treatment of cardiovascular disorders and other diseases. Hybridization of well established calcium antagonist subclasses was an attempt to optimize their pharmacological profile. The intension of this study was to investigate the electrophysiological properties of MM 10 and MM 11 two newly synthesized compounds structurally closely related to KT-362 (5- [3- [[2- (3,4-dimethoxyphenyl) ethyl] amino] -1-oxopropyl] -2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine fumarate) in various isolated guinea pig heart muscle preparations by means of the conventional intracellular microelectrode technique. MM 10 (2, 3-dihydro-1- [N- [2- (3, 4-dimethoxyphenyl) ethyl] -N-methylaminoacetyl] -1H-pyrido [2, 3-b] [1, 4] -thiazine fumarate) and MM 11 (2, 3-dihydro-1- [N- [2- (3,4-dimethoxyphenyl) ethyl] -N-methylaminopropionyl] -1H-pyrido [2, 3-b] [1,4] thiazine fumarate) exerted very similar effects though the action of MM 11 was more pronounced. Whereas action potential amplitude and maximum upstroke velocity (V_<max>) in papillary muscle, left atria and spontaneously beating Purkinje fibers was not affected by the compounds in a concentration range from 3 to 30 μmol/l, action potential duration at 90% time to repolarization was significantly prolonged in a concentration-dependent manner. Action potential duration at 20% time to repolarization was decreased in spontaneously beating Purkinje fibers and remained unchanged in papillary muscles and left atria. In sinoatrial nodes both compounds reduced rate of activity, action potential amplitude, maximum upstroke velocity and slope of slow diastolic depolarization while time to repolarization was prolonged. In 3 out of 6 experiments with spontaneously beating Purkinje fibers, MM 11 (30μmol/l) led to the occurrence of early afterdepolarizations with a take off potential between -50 and -60 mV. All observed effects were completely reversible during washout with drug-free physiological salt solution. From these results it was concluded that both compounds in addition to their calcium antagonistic properties might depress repolarizing potassium currents. In contrast to the mother compound KT-362 they do not seem to affect the fast sodium inward current. Replacement of the benzothiazepine nucleus by a pyridothiazine structure may weaken or even eliminate sodium channel blocking ability. Shortening of the side chain might result in a general loss in activity.

• 公益社団法人日本薬学会の論文
• 2004-09-01

著者

• Schade B

  Department Of Pharmacology And Toxicology University Of Vienna

• SCHADE Bettina

  Department of Pharmacology and Toxicology, University of Vienna

• ERKER Thomas

  Department of Pharmaceutical Chemistry, University of Vienna

• WEBER Manuela

  Department of Pharmaceutical Chemistry, University of Vienna

• STUDENIK Christian

  Department of Pharmacology and Toxicology, University of Vienna

• Studenik C

  Department Of Pharmacology And Toxicology University Of Vienna

• Erker Thomas

  Dep. Of Medicinal Chemistry Univ. Of Vienna

• Erker Thomas

  Department Of Medicinal Chemistry University Of Vienna

• Weber Manuela

  Department Of Pharmaceutical Chemistry University Of Vienna

関連論文

• Effects of Novel Synthesized Pyridothiazines on Various Guinea Pig Heart Muscle Preparations(Pharmacology)
• Synthesis of Novel Curcumin Analogues and Their Evaluation as Selective Cyclooxygenase-1 (COX-1) Inhibitors

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