Open AccessNa+ channels as sites of action of the cardioactive agent DPI 201-106 with agonist and antagonist enantiomers.
Author(s) -
Georges Romey,
Ulrich Quast,
David Pauron,
Christian Frelin,
JeanFrançois Renaud,
Michel Lazdunski
Publication year - 1987
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.84.3.896
Subject(s) - enantiomer , chemistry , dissociation constant , batrachotoxin , stereochemistry , biophysics , antagonist , tetrodotoxin , agonist , sodium channel , ion channel , pharmacology , biochemistry , sodium , biology , receptor , organic chemistry
This paper shows the interaction of the cardiotonic agent 4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole- 2-carbonitrile (DPI 201-106) and its optic enantiomers R-DPI (205-429) and S-DPI (205-430) with the Na+ channel of a variety of excitable cells. Voltage-clamp experiments show that DPI 201-106 acts on neuroblastoma cells and rat cardiac cells. S-DPI (205-430) increases the peak Na+ current, slows down the kinetics of Na+ channel inactivation, and is cardiotonic on heart cells. Conversely, R-DPI (205-429) reduces the peak Na+ current and blocks Na+ channel activity and cardiac contractions. Binding experiments using radioactively labeled toxins indicate that DPI 201-106 and its enantiomers do not interact with sites already identified for tetrodotoxin or sea anemone and scorpion toxins. DPI 201-106 and its enantiomers inhibit binding of a 3H-labeled batrachotoxin derivative, [3H]batrachotoxinin A 20-alpha-benzoate, to brain membranes. The dissociation constant of the complex formed between the Na+ channel and both R-DPI and S-DPI is Kd congruent to 100 nM. 22Na+ uptake experiments using different cell types have shown that R and S enantiomers of DPI 201-106 are active on the different Na+ channel subtypes with similar IC50 values. These results are discussed in relation with the cardiotonic properties of DPI 201-106 that are not accompanied by cardiotoxic effects.