Structure−Activity Relationships of Dimethindene Derivatives as New M₂-Selective Muscarinic Receptor Antagonists

Abstract

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 [(3)H]N-methylscopolamine ([(3)H]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.

Synthesis and Insecticidal Activity of Mesoionic Pyrido[1,2-α]pyrimidinone Derivatives Containing a Neonicotinoid Moiety

“…Intermediates A , B , and C were prepared according to the reported methods [ 38 , 39 , 40 , 41 , 42 , 43 ]. First, 2-chloro-5-chloromethylpyridine was slowly added to the aqueous solution of NaHCO 3 and 2-aminopyridine.…”

Ефективність Антигістамінних Препаратів I Покоління При Лікуванні Алергічних Захворювань У Дітей

“…Централь-ная холинолитическая активность препарата спо-собствует снижению стимуляции вестибулярных рецепторов и угнетению функции лабиринта, что обеспечивает противорвотный и противоукачиваю-щий эффект препарата. Выраженные холинолити-ческие эффекты (тахикардия, тошнота, возбужде-ние) при применении препарата в терапевтических дозах практически не развиваются [23].…”

Ring-closing metathesis for the synthesis of substituted indenols, indenones, indanones and indenes: Tandem RCM-dehydrogenative oxidation and RCM-formal redox isomerization

“…A topical example demonstrating a pharmaceutical application of an indanone compound would be flusolide 11, another potent and selective COX-2 inhibitor [9]. A representative of a medicinal indene is racemic dimethindene 12, a compound which penetrates readily into the brain; analogues of this compound have been investigated as muscarinic and histaminic H 1 receptor antagonists [10] (Fig. 3).…”