Abstract
The present study was designed to determine the in vitro affinity profile of ( R)-(−)-dimethindene and ( S)-(+)-dimethindene at muscarinic receptor subtypes using both functional and binding assays. In addition, the racemate was investigated in functional studies. The functional muscarinic receptors studied were putative M 1 receptors in rabbit vas deferens and rat duodenum, M 2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M 3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H 1 antagonism by ( R)-(−)- and ( S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OK 1 cells (M 1), rat heart (M 2), pancreas (M 3) and striatum (M 4). The results demonstrate that ( S)-(+)-dimethindene is a potent M 2-selective muscarinic receptor antagonist ( pA 2 = 7.86 7.74 ; p K i = 7.78) with lower affinities for the muscarinic M 1 ( pA 2 = 6.83 6.36 ; p K i = 7.08), the M 3 ( pA 2 = 6.92 6.96 ; p K i = 6.70) and the M 4 receptors (p K i = 7.00), respectively. The ( S)-(+)-enantiomer was more potent (up to 41-fold) than the ( R)-(−)-enantiomer in all muscarinic assays. In contrast, the stereoselectivity was inverse at histamine H 1 receptors, the ( R)-(−)-enantiomer being the eutomer (pA 2 = 9.42; pA 2 (S)- isomer = 7.48 ). In conclusion, ( S)-(+)-dimethindene is a useful tool to investigate muscarinic receptor heterogeneity. In addition, this lipophilic compound might become the starting point for the development of M 2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M 2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M 2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.
Published Version
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