Muscarinic Acetylcholine Receptors

Abstract

The five muscarinic acetylcholine receptors (M 1 –M 5 mAChRs) are prototypical members of the superfamily of G protein‐coupled receptors. The M 1 –M 5 mAChRs regulate an extraordinarily large number of central and peripheral functions. The first part of this chapter primarily focuses on how mAChRs function at a molecular level, the diversity of cellular responses following mAChR activation, and the mechanisms that are involved in regulating mAChR activity. The second part of this chapter summarizes recent results obtained with mutant mouse strains deficient in specific mAChR subtypes. These studies have led to a wealth of novel information about the physiological and pathophysiological roles of the individual mAChRs which may pave the way toward the development of novel, clinically useful muscarinic drugs.

Probing Structural Requirements of Positive Allosteric Modulators of the M4 Muscarinic Receptor

“…The novel monocyclic series 9a− c,e,g,h,k,l,p exhibited no allosteric modulatory effects. It is noteworthy that all synthesized target ligands that demonstrated positive allosteric modulation of the M 4 mAChR also exhibited intrinsic agonism (τ B ) at the allosteric site in their own right, a pharmacological feature also observed for the M 4 PAM (2). The compounds that exhibited the most promising affinity, cooperativity, and intrinsic efficacy profiles compared to the Vanderbilt University reference compounds 1a and 1i included the 3-fluoro (1h), the 3-fluoro-4-methoxy (1n), and the 2,3-difluoro-4-methoxy (1p) analogues.…”

“…Each of these subtypes is distributed throughout the periphery and central nervous system (CNS). The M 1 and M 4 subtypes have been of particular interest for the treatment of a range of CNS disorders, as they are abundantly expressed in the forebrain, including the striatum, cerebral cortex, and hippocampus, , and have been implicated in neuropsychiatric disorders such as Alzheimer’s disease and schizophrenia. Importantly, xanomeline (Figure ), an M 1 /M 4 -preferring orthosteric agonist, was introduced into clinical trials and exhibited dose-dependent improvements in cognitive deficits and positive symptoms (e.g., hallucinations, delusions) associated with schizophrenia .…”

Synthesis and Pharmacological Evaluation of M4 Muscarinic Receptor Positive Allosteric Modulators Derived from VU10004

“…16 mp 81−84 °C]. 1 H NMR (CDCl 3 ) δ 0.56−0.60 (m, 2H), 0.81−0.86 (m, 2H), 2.72−2.79 (m, 1H), 4.03 (s, 2H), 6.67 (br s, 1H). 13 C NMR (CDCl 3 ) δ 6.46 (CH 2 ), 6.46 (CH 2 ), 22.8 (CH), 42.5 (CH 2 ), 167.3 (C).…”

“…T he M 4 muscarinic acetylcholine receptor (mAChR), one of the five subtypes of the mAChRs, is a promising target for the alleviation of numerous symptoms associated with schizophrenia. 1 However, due to the high amino acid conservation between each of the mAChR subtypes, orthosteric ligands such as xanomeline 2 (Figure 1), which exhibits promising alleviation of positive and cognitive symptoms but possesses a poor side effect profile, are not actively pursued as treatments for CNS disorders. Allosteric ligands, such as 3amino-5-chloro-N-cyclopropyl-6-methoxy-4-methylthieno [2,3b]pyridine-2-carboxamide (LY2033298, 1) 3 (Figure 1), have been identified for the M 4 mAChR to overcome the difficulties in the discovery of subtype selective ligands.…”

Structure–Activity Studies of Diazabicyclo[3.3.0]octane-Substituted Pyrazines and Pyridines as Potent α4β2 Nicotinic Acetylcholine Receptor Ligands

“…Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels that have emerged as important targets in drug discovery. , nAChRs are activated by the endogenous neurotrasmitter acetylcholine (ACh) and the natural alkaloid nicotine . The other major class of acetylcholine receptors are the muscarinic acetylcholine receptors (mAChRs). − nAChR ligands have been explored for the treatment of Alzheimer’s disease, Parkinson’s disease, Tourette’s syndrome, schizophrenia, nicotine addiction, pain, various other central nervous system (CNS) disorders, and even non-CNS disorders such as cancer. − Modulating the activity of nAChRs offers potential for the development of new drugs in areas of significant unmet medical need …”