Structure-Activity Relationships of Dimethindene Derivatives as New M_2-Selective Muscarinic Receptor Antagonists

摘要

A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H_1 receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M_1-M_5) and for human histamine H_1 receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [~3V]N-methylscopolamine ([~3H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M_2 receptors ((S)-dimethindene: pK_i = 7.52; (-)-19: pK_i = 7.37) with an improved selectivity pattern ((S)-dimethindene: M_2/M_1 = 6-fold, M_2/M_3 = 5-fold, M_2/M_4 = 10-fold, M_2/M_5 = 25-fold; (-)-19: M_2/M_1 = 36-fold, M_2/M_3 = 96-fold, M_2/M_4 = 42-fold, M_2/M_5 = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H_1 receptors (pK_i = 5.61) than (S)-dimethindene (pK_i = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pK_i/M_2 = 7.49), which also exhibits a higher M_2 selectivity (M_2/M_1 = 19-fold; M_2/M_3 = 22-fold; M_2/M_4 = 13-fold; M_2/M_5 = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H_1 receptors (pK_i = 8.14). The compound with the highest affinity for M_2 receptors (pK_i = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M_2 receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M_2 receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M_2-selective muscarinic antagonists useful for quantifying M_2 receptors in the central nervous system with positron emission tomography imaging.