Electrophysiological Effects of Newly Synthesized 1,4-Pyridothiazepines on Various Guinea Pig Heart Muscle Preparations

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概要

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• Slow channel blockers play a major role in the treatment of cardiovascular disease. The intention of this study was to investigate the electrophysiological properties of MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4-tetrahydropyrido[2,3-b][1,4]thiazepine fumarate) and MM 6 (1-[N-[2-'3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropionyl]-1,2,3,4-tetrahydropyrido[2,3-b][1,4]thiazepine fumarate), two newly synthesized compounds structurally related to KT-362 (5-[3-[[2-(3,4-dimethoxy-phenyl)ethyl]-amino]-1-oxopropyl]-2,3,4,5-tetra-hydro-1,5-benzothiazepine fumarate), by means of the conventional intracellular microelectrode technique. In various guinea pig heart muscle preparations, MM 4 and MM 6 exerted very similar effects though the action of MM 6 was more pronounced. In a concentration range from 3 to 100 μmol/l the compounds did not produce any significant change in transmembrane action potential parameters of papillary muscle and left atria, whereas the action potential duration at 20% and 50% time to repolarization in spontaneously beating Purkinje fibers was significantly shortened. In sinoatrial nodes action potential amplitude, V_<max>, rate of activity and slope of slow diastolic depolarization were decreased, whereas the time to 50% and 90% repolarization was significantly prolonged. A decrease in the slow calcium inward current may account for the observed effects. In contrast to KT-362,MM 4 and MM 6 do not seem to affect the fast sodium inward current. It was concluded that replacement of the 1,5-benzothiazepine nucleus by a 1,4-pyridothiazepine structure and/or methylation of the side chain may weaken or even eliminate sodium channel blocking ability while calcium antagonistic characteristics are preserved. Shortening of the side chain might result in a general loss of activity.

• 公益社団法人日本薬学会の論文
• 1999-01-15

著者

• Schade Bettina

  Institute Of Pharmacology And Toxicology University Of Vienna

• Schade Bettina

  Institute Of Parmacology And Toxicology University Of Vienna

関連論文

• Electrophysiological Effects of Newly Synthesized 1,4-Pyridothiazepines on Various Guinea Pig Heart Muscle Preparations
• Effects of Novel Pyridothiazepines and Pyridothiazines on Contractility of Isolated Guinea-Pig Heart Muscle and Vascular Smooth Muscle Preparations

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