Molekulare Allianz – von orthosterischen und allosterischen Liganden zu dualsterischen/bitopischen Agonisten G‐Protein‐gekoppelter Rezeptoren

Mohr, Klaus; Schmitz, Jens; Schrage, R; Tränkle, Christian; Holzgrabe, Ulrike

doi:10.1002/ange.201205315

Cited by 7 publications

(1 citation statement)

References 68 publications

(96 reference statements)

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“…While orthosteric site sequence homology is high between all mAChR subtypes, in the extracellular parts of the transmembrane domains and extracellular loops of these receptors, there is a low degree of sequence homology. In summary, the interactions of ligands with receptors can occur as follows (Mohr et al, 2013): 1) positive allosteric modulators (PAMs) increase the affinity or efficacy of an orthosteric ligand or orthosteric agonist-receptor complex, increase the equilibrium binding of the simultaneously bound endogenous or exogenous orthosteric ligand, enhance either the affinity of an orthosteric agonist or lower the activation barrier for the transition from the inactive to the active conformation of the receptor, 2) negative allosteric modulators (NAMs) decrease the affinity or efficacy of an orthosteric ligand or orthosteric agonist-receptor complex, inducing a rightward shift of the concentration-effect curve of the endogenous agonist (as an example), 3) neutral allosteric ligands (NALs) bind to an allosteric site but have no effect on the affinity or efficacy of orthosteric or allosteric ligands, and 4) allosteric agonists activate the receptors themselves.…”

Section: Muscarinic Receptor Allosteric Ligandsmentioning

confidence: 99%

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Mysliveček¹

2022

Front. Physiol.

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Muscarinic receptors (mAChRs) are typical members of the G protein-coupled receptor (GPCR) family and exist in five subtypes from M1 to M5. Muscarinic receptor subtypes do not sufficiently differ in affinity to orthosteric antagonists or agonists; therefore, the analysis of receptor subtypes is complicated, and misinterpretations can occur. Usually, when researchers mainly specialized in CNS and peripheral functions aim to study mAChR involvement in behavior, learning, spinal locomotor networks, biological rhythms, cardiovascular physiology, bronchoconstriction, gastrointestinal tract functions, schizophrenia, and Parkinson’s disease, they use orthosteric ligands and they do not use allosteric ligands. Moreover, they usually rely on manufacturers’ claims that could be misleading. This review aimed to call the attention of researchers not deeply focused on mAChR pharmacology to this fact. Importantly, limited selective binding is not only a property of mAChRs but is a general attribute of most neurotransmitter receptors. In this review, we want to give an overview of the most common off-targets for established mAChR ligands. In this context, an important point is a mention the tremendous knowledge gap on off-targets for novel compounds compared to very well-established ligands. Therefore, we will summarize reported affinities and give an outline of strategies to investigate the subtype’s function, thereby avoiding ambiguous results. Despite that, the multitargeting nature of drugs acting also on mAChR could be an advantage when treating such diseases as schizophrenia. Antipsychotics are a perfect example of a multitargeting advantage in treatment. A promising strategy is the use of allosteric ligands, although some of these ligands have also been shown to exhibit limited selectivity. Another new direction in the development of muscarinic selective ligands is functionally selective and biased agonists. The possible selective ligands, usually allosteric, will also be listed. To overcome the limited selectivity of orthosteric ligands, the recommended process is to carefully examine the presence of respective subtypes in specific tissues via knockout studies, carefully apply “specific” agonists/antagonists at appropriate concentrations and then calculate the probability of a specific subtype involvement in specific functions. This could help interested researchers aiming to study the central nervous system functions mediated by the muscarinic receptor.

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Section: Muscarinic Receptor Allosteric Ligandsmentioning

confidence: 99%

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Mysliveček¹

2022

Front. Physiol.

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Ein photoschaltbarer Ligand zur Regulierung der Rezeptoraktivierung

et al. 2017

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Über die Art und den zeitlichen Verlauf der Aktivierung von G-Protein-gekoppelten Rezeptoren (GPCRs), insbesondere der muskarinischen Acetylcholinrezeptoren (mACh-oder M-Rezeptoren), ist trotz der enormen therapeutischen Relevanz von M-Rezeptoren und GPCRs wenig bekannt. In der vorliegenden Arbeit haben wir deshalb einen dualsteren Liganden eingesetzt, der sowohl mit der orthosteren Bindungsstelle des Rezeptors,d .h.d erjenigen des Neurotransmitters,a ls auch mit einer allosteren Bindungsstelle interagiert, wobei synthetischeine photoschaltbare (photochrome) Azobenzoleinheit eingebaut wurde.W ir haben die photophysikalischen Eigenschaften des BQCAAI benannten Liganden charakterisiert und seine Einsetzbarkeit als pharmakologisches Werkzeug mit einem Satz von FRET-Techniken am M 1 -Rezeptor untersucht. BQCAAI stellt den ersten photoschaltbaren dualsteren Liganden dar,und seine Aktivitätkann durchLicht reguliert werden. Wirh aben BQCAAI eingesetzt, um den zeitlichen Ablauf verschiedener Prozesse der Rezeptoraktivierung zu untersuchen.

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A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy

et al. 2017

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The investigation of the mode and time course of the activation of G-protein-coupled receptors (GPCRs), in particular muscarinic acetylcholine (mACh or M) receptors, is still in its infancy despite the tremendous therapeutic relevance of M receptors and GPCRs in general. We herein made use of a dualsteric ligand that can concomitantly interact with the orthosteric, that is, the neurotransmitter, binding site and an allosteric one. We synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated by light. We also applied BQCCAI to investigate the time course of several receptor activation processes.

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Molekulare Allianz – von orthosterischen und allosterischen Liganden zu dualsterischen/bitopischen Agonisten G‐Protein‐gekoppelter Rezeptoren

Cited by 7 publications

References 68 publications

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Ein photoschaltbarer Ligand zur Regulierung der Rezeptoraktivierung

A Photoswitchable Dualsteric Ligand Controlling Receptor Efficacy

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