Abstract
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.
Highlights
Slow metabotropic responses to acetylcholine are mediated by muscarinic receptors
G-protein-coupled receptor (GPCR) allosteric modulators bind to a site on the receptor that is spatially distinct from that of the endogenous transmitter, acetylcholine, in the case of muscarinic receptors
While the majority of known muscarinic allosteric ligands bind to the site between the o2 and o3 loops, sterol-based WIN-compounds have been found to interact with gallamine and strychnine in a non-competitive manner [36]
Summary
Slow metabotropic responses to acetylcholine are mediated by muscarinic receptors. Five distinct subtypes of muscarinic acetylcholine receptors (M1–M5) have been identified in the human genome [1]. GPCR allosteric modulators bind to a site on the receptor that is spatially distinct from that of the endogenous transmitter, acetylcholine, in the case of muscarinic receptors. NNeeggaattiivvee aalllloosstteerriicc mmoodduullaattoorrss ((NNAAMM)) tthhaatt ddeeccrreeaassee tthhee aaffiffinniittyyooffoorrththoossteterirciclilgiganandds;sa; nadnd3.3N. Selectivity by Targeting Less Conserved Domains on the Receptor wherMMe tuuhsseccaaorrriitnnhiioccsrrteeeccreiecppbttooinrrdssuiunbbgttyysppiteeessissshhloaarcreaethheidigg.hhOssnttrrutuhccettuuorrtaahllehhroohmmanoodlloo,ggdyyoiminnattihhneestotrrauantnsosmmf teehmmebbmrraaennmeebddroaomnmeaaaiinnress where the orthosteric binding site is located. Targeting allosteric domains allows achieving binding selectivity for certain receptor lseusbstcyopnessetrovethde. While the majority of known muscarinic allosteric ligands bind to the site between the o2 and o3 loops, sterol-based WIN-compounds have been found to interact with gallamine and strychnine in a non-competitive manner [36]. Cholesterol allosterically modulates the binding and function of muscarinic receptors [37,38,39,40]. How many cholesterol binding sites muscarinic receptors do have and whether sterol-based WIN-compounds bind to the cholesterol-binding site remains to be elucidated
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