Muscarinic Receptor Agonists and Antagonists

Abstract

A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

Muscarinic receptor binding activity of polyoxygenated flavones from Melicope subunifoliolata

“…Selective M1 agonists have also been shown to be potential disease-modifying agents in Alzheimer's disease (Eglen, 1998;Mutschler et al, 1995). This is mediated by the stimulation of the postsynaptic M1 receptors involved in memory and inhibition of amyloid deposition implicated in the pathogenesis of Alzheimer's disease (Broadley and Kelly, 2001). Alternatively, antagonists of central presynaptic M2 receptors improve cognition in Alzheimer's patients by increasing the central release of acetylcholine (Lai et al, 2001;Teaktong et al, 2005).…”

“…For example, more selective agonists and antagonists for muscarinic receptor subtypes (M1-M5) with reduced side effects and improved therapeutic activities have been introduced. These include selective muscarinic receptor antagonists developed for antiulcer activity (Telenzepine; M1/M4 selective; Byk), bradycardia (Otenzepad; M2/M4 selective; Boehringer Ingelheim), irritable bowel syndrome (Darifenacin; M3/M1 selective; Pfizer), and antibronchospastic activity (Rispenzepine; M3/M1 selective; Dompe) (Broadley and Kelly, 2001;Eglen, 1998). Selective M1 agonists have also been shown to be potential disease-modifying agents in Alzheimer's disease (Eglen, 1998;Mutschler et al, 1995).…”

“…However, the approach of searching for partial agonists and antagonists, and exploring the subtype distribution in tissues has been more successful in producing useful therapeutic compounds (Broadley and Kelly, 2001;Tumiatti et al, 2007). For example, more selective agonists and antagonists for muscarinic receptor subtypes (M1-M5) with reduced side effects and improved therapeutic activities have been introduced.…”

“…This is mainly caused by their non-selectivity towards the different muscarinic receptor subtypes designated as M1-M5. Furthermore, different muscarinic receptor subtypes have different tissue distribution (Broadley and Kelly, 2001;Ishii and Kurachi, 2006).…”

Selective blockade of central M1 muscarinic cholinergic receptors with pirenzepine impairs cardiovascular and respiratory function in rats with acute hemorrhage

“…Published data show that activation of muscarinic cholinergic structures in the brain during shock is followed by inhibition of cardiovascular and respiratory function [1,3,10]. The role of various subtypes of central M-CR [9] in the pathogenesis of hemodynamic and respiratory dysfunction under shock conditions remains unknown.…”