Dualsteric ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to both, the orthosteric transmitter binding site and an additional allosteric binding area of a receptor protein. This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single ligand molecule. The orthosteric interaction provides high affinity binding and activation of receptors. The allosteric interaction yields receptor subtype-selectivity and, in addition, may modulate both, efficacy and intracellular signalling pathway activation. Insight into the spatial arrangement of the orthosteric and the allosteric site is far advanced in the muscarinic acetylcholine receptor, and the design of dualsteric muscarinic agonists has now been accomplished. Using the muscarinic receptor as a paradigm, this review summarizes the way from suggestive evidence for an orthosteric/allosteric overlap binding to the rational design and experimental validation of dualsteric ligands. As allosteric interactions are increasingly described for GPCRs and as insight into the spatial geometry of ligand/GPCR-complexes is growing impressively, the rational design of dua...Continue Reading
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Interactions of orthosteric and allosteric ligands with [3H]dimethyl-W84 at the common allosteric site of muscarinic M2 receptors
Development of a new type of allosteric modulator of muscarinic receptors: hybrids of the antagonist AF-DX 384 and the hexamethonio derivative W84
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Mutational disruption of a conserved disulfide bond in muscarinic acetylcholine receptors attenuates positive homotropic cooperativity between multiple allosteric sites and has subtype-dependent effects on the affinities of muscarinic allosteric ligands
A novel multivalent ligand that bridges the allosteric and orthosteric binding sites of the M2 muscarinic receptor
Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands
Allosteric small molecules unveil a role of an extracellular E2/transmembrane helix 7 junction for G protein-coupled receptor activation
Autoantibodies enhance agonist action and binding to cardiac muscarinic receptors in chronic Chagas' disease
A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand
Allosteric ligands for G protein-coupled receptors: a novel strategy with attractive therapeutic opportunities
Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors
Simplified models for heterobivalent ligand binding: when are they applicable and which are the factors that affect their target residence time
Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist
Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity
On the 'micro'-pharmacodynamic and pharmacokinetic mechanisms that contribute to long-lasting drug action
Dualsteric GPCR targeting and functional selectivity: the paradigmatic M(2) muscarinic acetylcholine receptor
Allosteric modulators of rhodopsin-like G protein-coupled receptors: opportunities in drug development
Mapping the druggable allosteric space of G-protein coupled receptors: a fragment-based molecular dynamics approach
A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design
Biased agonism at G protein-coupled receptors: the promise and the challenges--a medicinal chemistry perspective
Avidity and positive allosteric modulation/cooperativity act hand in hand to increase the residence time of bivalent receptor ligands
Pharmacologically distinct phenotypes of α1B -adrenoceptors: variation in binding and functional affinities for antagonists
On the different experimental manifestations of two-state 'induced-fit' binding of drugs to their cellular targets
'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models
Kinetic Aspects of the Interaction between Ligand and G Protein-Coupled Receptor: The Case of the Adenosine Receptors
Multivalent approaches and beyond: novel tools for the investigation of dopamine D2 receptor pharmacology
Molecular alliance-from orthosteric and allosteric ligands to dualsteric/bitopic agonists at G protein coupled receptors
Fishing for accessory binding sites at GPCRs with 'loop-hooks' - an approach towards selectivity? Part I
Exploration of the orthosteric/allosteric interface in human M1 muscarinic receptors by bitopic fluorescent ligands
Designing Hybrids Targeting the Cholinergic System by Modulating the Muscarinic and Nicotinic Receptors: A Concept to Treat Alzheimer's Disease
Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays.
Rational Modification of the Biological Profile of GPCR Ligands through Combination with Other Biologically Active Moieties
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Hybrid molecules from xanomeline and tacrine: enhanced tacrine actions on cholinesterases and muscarinic M1 receptors
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