Muscarinic acetylcholine receptors are membrane receptors involved in many physiological processes. Malfunction of muscarinic signaling is a cause of various internal diseases, as well as psychiatric and neurologic conditions. Cholesterol, neurosteroids, neuroactive steroids, and steroid hormones are molecules of steroid origin that, besides having well-known genomic effects, also modulate membrane proteins including muscarinic acetylcholine receptors. Here, we review current knowledge on the allosteric modulation of muscarinic receptors by these steroids. We give a perspective on the research on the non-genomic effects of steroidal compounds on muscarinic receptors and drug development, with an aim to ultimately exploit such knowledge.

• Klíčová slova
• allosteric modulation, cholesterol, muscarinic receptors, neuroactive steroids, neurosteroids,
• MeSH
• cholesterol MeSH
• hormony metabolismus   MeSH
• neurosteroidy * farmakologie   MeSH
• receptory muskarinové MeSH
• steroidy farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cholesterol MeSH
• hormony MeSH
• neurosteroidy * MeSH
• receptory muskarinové MeSH
• steroidy MeSH

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30% of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Additionally, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

• Klíčová slova
• GPCRs, allosteric modulation, cholesterol,
• MeSH
• alosterická regulace MeSH
• anticholesteremika farmakologie   terapeutické užití   MeSH
• buněčná membrána metabolismus   MeSH
• cholesterol chemie   metabolismus   MeSH
• cílená molekulární terapie metody   MeSH
• lidé MeSH
• ligandy MeSH
• receptory spřažené s G-proteiny chemie   klasifikace   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• anticholesteremika MeSH
• cholesterol MeSH
• ligandy MeSH
• receptory spřažené s G-proteiny MeSH

BACKGROUND AND PURPOSE: More than 30% of currently marketed medications act via GPCRs. Thus, GPCRs represent one of the most important pharmacotherapeutic targets. In contrast to traditional agonists activating multiple signalling pathways, agonists activating a single signalling pathway represent a new generation of drugs with increased specificity and fewer adverse effects. EXPERIMENTAL APPROACH: We have synthesized novel agonists of muscarinic ACh receptors and tested their binding and function (on levels of cAMP and inositol phosphates) in CHO cells expressing individual subtypes of muscarinic receptors, primary cultures of rat aortic smooth muscle cells and suspensions of digested native tissues from rats. Binding of the novel compounds to M2 receptors was modelled in silico. KEY RESULTS: Two of the tested new compounds (1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium and 1-methyl-1-(thiophen-2-ylmethyl)-3,6-dihydro-2H-pyridinium) only inhibited cAMP synthesis in CHO cells, primary cultures, and native tissues, with selectivity for M2 muscarinic receptors and displaying bias towards the Gi signalling pathway at all subtypes of muscarinic receptors. Molecular modelling revealed interactions with the orthosteric binding site in a way specific for a given agonist followed by agonist-specific changes in the conformation of the receptor. CONCLUSIONS AND IMPLICATIONS: The identified compounds may serve as lead structures in the search for novel non-steroidal and non-opioid analgesics acting via M2 and M4 muscarinic receptors with reduced side effects associated with activation of the phospholipase C signalling pathway.

• MeSH
• agonisté muskarinových receptorů * farmakologie   MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• křečci praví MeSH
• krysa rodu Rattus MeSH
• receptor muskarinový M2 MeSH
• receptory muskarinové * MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté muskarinových receptorů * MeSH
• antagonisté muskarinových receptorů MeSH
• receptor muskarinový M2 MeSH
• receptory muskarinové * MeSH

Allosteric modulators are ligands that bind to a site on the receptor that is spatially separated from the orthosteric binding site for the endogenous neurotransmitter. Allosteric modulators modulate the binding affinity, potency, and efficacy of orthosteric ligands. Muscarinic acetylcholine receptors are prototypical allosterically-modulated G-protein-coupled receptors. They are a potential therapeutic target for the treatment of psychiatric, neurologic, and internal diseases like schizophrenia, Alzheimer's disease, Huntington disease, type 2 diabetes, or chronic pulmonary obstruction. Here, we reviewed the progress made during the last decade in our understanding of their mechanisms of binding, allosteric modulation, and in vivo actions in order to understand the translational impact of studying this important class of pharmacological agents. We overviewed newly developed allosteric modulators of muscarinic receptors as well as new spin-off ideas like bitopic ligands combining allosteric and orthosteric moieties and photo-switchable ligands based on bitopic agents.

• Klíčová slova
• acetylcholine, allosteric modulation, muscarinic receptors,
• MeSH
• agonisté muskarinových receptorů metabolismus   MeSH
• alosterická regulace fyziologie   MeSH
• antagonisté muskarinových receptorů metabolismus   MeSH
• lidé MeSH
• ligandy MeSH
• receptory muskarinové metabolismus   fyziologie   MeSH
• receptory spřažené s G-proteiny MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• agonisté muskarinových receptorů MeSH
• antagonisté muskarinových receptorů MeSH
• ligandy MeSH
• receptory muskarinové MeSH
• receptory spřažené s G-proteiny MeSH