title: The (S)-(+)-enantiomer of dimethindene: a novel M2-selective muscarinic receptor antagonist.
abstract: The present study was designed to determine 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 M1 receptors in rabbit vas deferens and rat duodenum, M2 receptors in guinea-pig left atria and rabbit vas deferens, as well as M3 receptors in guinea-pig ileum and trachea. Furthermore, the histamine H1 antagonism by (R)-(-)- and (S)-(+)-dimethindene has been examined in guinea-pig ileum. Muscarinic binding selectivity was assessed in homogenates from human neuroblastoma NB-OF 1 cells (M1), rat heart (M2), pancreas (3) and striatum (M4). The results demonstrate that (S)-(+)-dimethindene is a potent M2-selective muscarinic receptor antagonist (pA2 = 7.86/7.74; pKi = 7.78) with lower affinities for the muscarinic M1 (pA2 = 6.83/6.36; pKi = 7.08), the M3 (pA2 = 6.92/6.96; pKi = 6.70) and the M4 receptors (pKi = 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 H1 receptors, the (R)-(-)-enantiomer being the eutomer (pA2 = 9.42; pA2/(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 M2-selective muscarinic receptor antagonists useful as diagnostic tools for quantifying muscarinic M2 receptors in the central nervous system with positron emission tomography imaging, and to test the hypothesis that muscarinic M2 receptor antagonists show beneficial effects in the treatment of cognitive disorders.
authors.affiliation: Department of Pharmacology, Biocentre Niederursel, University of Frankfurt, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Pfaff
authors.forename: C
authors.initials: C
authors.lastname: Hildebrandt
authors.forename: M
authors.initials: M
authors.lastname: Waelbroeck
authors.forename: X
authors.initials: X
authors.lastname: Hou
authors.forename: U
authors.initials: U
authors.lastname: Moser
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: G
authors.initials: G
authors.lastname: Lambrecht
mesh_terms: D000818:Animals; D004115:Dimethindene / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
chemical_list: D006634:Histamine H1 Antagonists; D018727:Muscarinic Antagonists; D004115:Dimethindene