Muscarinic agonists and antagonists in the treatment of Alzheimer's disease

The Predicted 3D Structures of the Human M1 Muscarinic Acetylcholine Receptor with Agonist or Antagonist Bound

“…The predicted binding site of all four antagonists is located between transmembrane (TM) helices 3, 4, 5, 6, and 7, whereas the three agonists prefer a site involving residues from TM3, TM6, and TM7. We find that Trp 157(4) contributes directly to antagonist binding, whereas Pro 159(4) provides an indirect conformational switch to position Trp 157 (4) in the binding site (the number in parentheses indicates the TM helix). This explains the large decrease in ligand binding affinity and signaling efficacy by mutations of Trp 157 (4) and Pro 159(4) not previously explained by homology models.…”

“…We find that Trp 157(4) contributes directly to antagonist binding, whereas Pro 159(4) provides an indirect conformational switch to position Trp 157 (4) in the binding site (the number in parentheses indicates the TM helix). This explains the large decrease in ligand binding affinity and signaling efficacy by mutations of Trp 157 (4) and Pro 159(4) not previously explained by homology models. We also found that Asp 105(3) and aromatic residues Tyr 381(6), Tyr 404 (7), and Tyr 408(7) are critical for binding the quaternary ammonium head group of the ligand through cation-p interactions.…”

“…[3] Significant effort has been focused on identifying M1 agonists and M2 antagonists as a potential treatment of Alzheimer's disease by stimulating the cholinergic system. [1,4] The rationale for developing M1 agonists is based on the role of acetylcholine in learning and memory function and the finding that cholinergic neurons degenerate in patients of Alzheimer's disease. The development of muscarinic M1 receptor agonists for the treatment of cognitive dysfunctions resulted in a series of drug candidates, but many were discontinued because of undesirable side effects from cross-reactivity to other receptor subtypes.…”

Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622

“…Significant efforts have been put forth to identify selective agonists, (Heinrich et al 2009;Greenlee et al 2001), however due to the high homology of the orthosteric ligand binding site, developing selective orthosteric or bitopic agonists has remained a challenge within the field. An alternative strategy to achieve receptor sub-type selectivity is through the identification of allosteric ligands, either positive allosteric modulators or allosteric agonists, which have the potential to bind to less-conserved regions distal to the orthosteric binding site (Davie et al, 2013;Kuduk and Beshore, 2012).…”

Development of an Efficient Therapeutic Agent for Alzheimer's Disease: Design and Synthesis of Dual Inhibitors of Acetylcholinesterase and Serotonin Transporter

“…These are: [1] AChE inhibitors, 13) which increase the level of ACh in the synaptic cleft [2] ACh precursors, 14) such as choline [3] ACh releasers, 15) which advance the release of ACh from presynapses [4] muscarinic agonists, 16) which activate muscarinic receptors on postsynapse [5] nicotinic agonists, 17) which activate nicotinic receptors on postsynapse Among these strategies, it is known that the only clinically effective strategy for the palliative treatment of AD is to inhibit AChE. 18) At present, several AChE inhibitors have successfully reached the market, such as tacrine (Cognex ® ), 19) donepezil (Aricept ® ), 20) rivastigmine (Exelon ® ) 21) and galanthamine (Reminyl ® ) 22) (Fig.…”