Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity

Matera, Carlo; Flammini, Lisa; Quadri, Marta; Vivo, Valentina; Ballabeni, Vigilio; Holzgrabe, Ulrike; Mohr, Klaus; Amici, Marco De; Barocelli, Elisabetta; Bertoni, Simona; Dallanoce, Clelia

doi:10.1016/j.ejmech.2014.01.032

Cited by 26 publications

(34 citation statements)

References 33 publications

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“…28 By designing bipharmacophoric ligands consisting of the M 2 -superagonist iperoxo 19 and a phthalimido-or naphthalimidopropylammonium moiety, which were found to bind to M 2 receptors with moderate selectivity, we had learned that subtype selectivity of ligand binding can be achieved by concomitantly addressing the allosteric and orthosteric site. 29 Compared to conventional agonists, including acetylcholine, these ligands are able to preferentially use one signaling pathway over others, hence displaying biased signaling. 4,5 In addition and most interestingly with respect to the current study, receptor binding of a bipharmacophoric compound may theoretically switch between a dualsteric and a purely allosteric orientation.…”

Section: ■ Introductionmentioning

confidence: 99%

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

et al. 2014

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Aiming to design partial agonists for a G-protein-coupled receptor based on dynamic ligand binding, we synthesized three different series of bipharmacophoric ligands composed of the orthosteric building blocks iperoxo and 1 linked to allosteric modulators (BQCA-derived compounds, BQCAd; TBPB-derived compound, TBPBd). Their interactions were studied with the human muscarinic acetylcholine M1-receptor (hM1) with respect to receptor binding and Gq-protein signaling. Results demonstrate that iperoxo/BQCAd (2, 3) and 1/BQCAd hybrids (4) act as M1 partial agonists, whereas 1/TBPBd hybrids (5) did not activate M1-receptors. Among the iperoxo/BQCAd-hybrids, spacer length in conjunction with the pattern of substitution tuned efficacy. Most interestingly, a model of dynamic ligand binding revealed that the spacer length of 2a and 3a controlled the probability of switch between the inactive purely allosteric and the active bitopic orthosteric/allosteric binding pose. In summary, dynamic ligand binding can be exploited in M1 receptors to design partial agonists with graded efficacy.

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Section: ■ Introductionmentioning

confidence: 99%

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

et al. 2014

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“…Besides being an interesting research tool, bitopic muscarinic ligands, consisting of the orthosteric and allosteric moiety, have also a translational potential. For example, bis(ammonio)alkane-type compounds (hybrid molecules of the orthosteric agonist iperoxo and allosteric moiety derived from naphmethonium or W84) can be used as non-opioid non-steroidal analgesics [69] or inhibitors of cell growth for glioblastoma therapy [70]. Besides being an interesting research tool, bitopic muscarinic ligands, consisting of the orthosteric and allosteric moiety, have also a translational potential.…”

Section: Novel Allosteric Modulatorsmentioning

confidence: 99%

Current Advances in Allosteric Modulation of Muscarinic Receptors

Jakubík

El‐Fakahany

2020

Biomolecules

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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.

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“…1B). As the allosteric fragments are derived from allosteric antagonists/inverse agonists, the purely allosteric binding pose stabilizes an inactive receptor conformation (Tränkle et al, 1998;Disingrini et al, 2006;Bock et al, 2014;Matera et al, 2014). In contrast, the dualsteric binding pose stabilizes active receptor conformations, because the orthosteric moieties are agonists (Dallanoce et al, 1999;Schrage et al, 2013;Bock et al, 2014).…”

Section: Distinct Binding Poses Of Dualsteric Ligands Maymentioning

confidence: 99%

A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

et al. 2017

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Protean agonists are of great pharmacological interest as their behavior may change in magnitude and direction depending on the constitutive activity of a receptor. Yet, this intriguing phenomenon has been poorly described and understood, due to the lack of stable experimental systems and design strategies. In this study, we overcome both limitations: First, we demonstrate that modulation of the ionic strength in a defined experimental set-up allows for analysis of G protein-coupled receptor activation in the absence and presence of a specific amount of spontaneous receptor activity using the muscarinic M acetylcholine receptor as a model. Second, we employ this assay system to show that a dualsteric design principle, that is, molecular probes, carrying two pharmacophores to simultaneously adopt orthosteric and allosteric topography within a G protein-coupled receptor, may represent a novel approach to achieve protean agonism. We pinpoint three molecular requirements within dualsteric compounds that elicit protean agonism at the muscarinic M acetylcholine receptor. Using radioligand-binding and functional assays, we posit that dynamic ligand binding may be the mechanism underlying protean agonism of dualsteric ligands. Our findings provide both new mechanistic insights into the still enigmatic phenomenon of protean agonism and a rationale for the design of such compounds for a G protein-coupled receptor.

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Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity

Cited by 26 publications

References 33 publications

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

Current Advances in Allosteric Modulation of Muscarinic Receptors

A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

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Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity

Cited by 26 publications

References 33 publications

Rational Design of Partial Agonists for the Muscarinic M1 Acetylcholine Receptor

Rational Design of Partial Agonists for the Muscarinic M1 Acetylcholine Receptor

Current Advances in Allosteric Modulation of Muscarinic Receptors

A New Molecular Mechanism To Engineer Protean Agonism at a G Protein–Coupled Receptor

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Product

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Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor

Rational Design of Partial Agonists for the Muscarinic M₁ Acetylcholine Receptor