Abstract
Stereoselective effects of mianserin and ORG3770 on serotonin 5-HT 3 receptors in mouse neuroblastoma N1E-115 cells have been investigated in radioligand binding and in whole-cell voltage clamp experiments. The specific binding of [ 3H]GR65630 to 5-HT 3 recognition sites in N1E-115 cell homogenates is reduced by mianserin and ORG3770 and their enantiomers. The p K i values of the more potent ( R)enantiomers of mianserin and ORG3770 are 8.44 and 8.62, respectively. The ( R)enantiomers of mianserin and ORG3770 are 15 and 37 times more potent than their respective( S)enantiomers. The racemates are only 1.9 and 3.3 times less potent than the corresponding ( R)enantiomers. In voltage clamp experiments the ( R)enantiomers block the 5-hydroxytryptamine(5-HT)-induced ion current with pIC 50 values of 8.52 for ( R)mianserin and 8.26 for the ( R)enantiomer of ORG3770. The ( R)enantiomers of mianserin and ORG3770 are 24 and 145 times more potent in blocking the 5-HT-induced ion current than their respective ( S)enantiomers. The racemates are 6 and 13 times less potent than the corresponding ( R)enantiomers. In addition, the block of 5-HT-induced ion current by the ( R)enantiomer of ORG3770 is partially reversed by a low concentration of its ( S)enantiomer. The results indicate that the two enantiomers block the 5-HT 3 receptor-mediated ion current in a mutually dependent manner.
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