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Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2’-butylamino)-4H- and 3-(3’-methyl-2’-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers

Authors
Publication Date
Keywords
  • Adenosine Triphosphate/Pharmacology
  • Animals
  • Aorta/Drug Effects
  • Cells
  • Cultured
  • Cyclic N-Oxides
  • Cyclic S-Oxides/Chemical Synthesis/Chemistry/Pharmacology
  • Drug Evaluation
  • Ion Channel Gating
  • Islets Of Langerhans/Drug Effects/Secretion
  • Magnetic Resonance Spectroscopy
  • Potassium Channels/Drug Effects
  • Pyridines/Chemical Synthesis/Chemistry/Pharmacology
  • Rats
  • Rats
  • Wistar
  • Spectrophotometry
  • Infrared
  • Stereoisomerism
  • Thiadiazines/Chemical Synthesis/Chemistry/Pharmacology
  • Human Health Sciences :: Pharmacy
  • Pharmacology & Toxicology [D20]
  • Sciences De La Santé Humaine :: Pharmacie
  • Pharmacologie & Toxicologie [D20]
Disciplines
  • Biology
  • Medicine
  • Pharmacology

Abstract

The preparation and the pharmacological evaluation of the R- and S-isomers of 3-(2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 42) and 3-(3-methyl-2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical purity was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) and chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isomer of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differences in their activity on pancreatic B-cells but significant differences in their activity on vascular smooth muscle cells: the R-isomer being sixfold more potent than its corresponding S-isomer. The R-isomer of BPDZ 42 was shown to be more potent than its corresponding S-isomer on the endocrine pancreas. S-BPDZ 44 as well as R- and S-BPDZ 42 were found to exhibit tissue selectivity for the pancreatic versus the vascular smooth muscle tissue.

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