Design and pharmacology of quinuclidine derivatives as M2-selective muscarinic receptor ligands

New Trends in the Design of Drugs Against Alzheimer's Disease

“…On the other hand, based on theoretical structure requirements for M 2 antagonism, compounds containing the benzofulvene core were synthesized; from this series emerge derivatives with a quinuclidine moiety and a pyridine residue such as (24) [27]. , an M 2 antagonist structurally related to atropine, was recently reported to have central antinociceptive and antiamnesic effects in mice and rats [28].…”

“…(27) was recently reported to be an M 2 antagonist, but exhibited lower affinity and showed a 10-fold selectivity for M 2 /M 1 [30].…”

Structural Modifications to Tetrahydropyridine-3-carboxylate Esters en Route to the Discovery of M5-Preferring Muscarinic Receptor Orthosteric Antagonists

“…Unlike allosteric binding sites, which are usually more divergent across subtypes, orthosteric ACh binding sites across the five mAcChR subtypes have been shown to be highly conserved at the amino acid sequence level (73–83% identity) . As such, selectivity among the mAcChR subtypes is likely based on conformational dissimilarities rather than upon single amino acid residues. − In fact, small molecule orthosteric antagonists with preference for an individual subtype have been reported for M 1 –M 4 but not M 5 (e.g., compound 3 for M 1 , 5 for M 2 , 6 for M 3 , and 7 for M 4 , Figure ), indicating the existence of sufficient differences among the agonist recognition sites on the five mAcChR subtypes allowing targeting of selective compounds to these sites.…”

A Simple and Mild Microwave-Based Synthesis of Novel Functionalized Benzofulvenes

“…While these methods have greatly improved our abilities to access a wealth of benzofulvene-based motifs, there is arguably room in this mix for a simple and effective synthetic solution. To that end we have been engaged in modifying and optimizing a traditional route to the benzofulvene core 10 by utilizing substituted indanones to produce known and many novel functionalized benzofulvenes in three simple synthetic steps (Scheme 1).…”