title: Na+ channels as sites of action of the cardioactive agent DPI 201-106 with agonist and antagonist enantiomers.
abstract: 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.
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002645:Chickens; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D009132:Muscles / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
chemical_list: D007473:Ion Channels; D010879:Piperazines; C046261:DPI 201-106; D012964:Sodium