Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT<sub>3</sub>) Subunit A Receptors

Alix, Katie; Khatri, Shailesh; Mosier, Philip D.; Casterlow, Samantha; Dong, Yan; Nyce, Heather L.; White, Michael M.; Schulte, Marvin K.; Dukat, Małgorzata

doi:10.1021/acschemneuro.6b00196

Cited by 10 publications

(27 citation statements)

References 45 publications

(86 reference statements)

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“…Some reports have described “superagonists” as compounds that have efficacy in the assay greater than that of the natural full agonist for membrane receptors, such as nicotinic acetylcholine receptors or adrenergic β 2 -receptors. − Therefore, the above data showed that compound 2 possesses agonistic ability superior to natural agonist OT, which indicated that it is a superagonist. This is the first example of a superagonist for OTR.…”

Section: Resultsmentioning

confidence: 94%

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

et al. 2019

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The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro7 of OT was replaced with N-(p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist (E Max = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16–24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.

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Section: Resultsmentioning

confidence: 94%

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

et al. 2019

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“…Movement of loop C has been proposed to have a central role in mechanistic models for Cys-loop receptor function. Specifically, binding of ligands that act as agonists have been proposed to contract loop C around the orthosteric binding site, while binding of ligands that act as antagonists do not induce constriction or induce a more extended orientation compared with the apo state (Celie et al, 2004;Hansen et al, 2005;(Brams et al, 2011), Kesters et al, 2013;Alix et al, 2016). This capping movement by loop C has been proposed as essential for promoting structural transitions toward the opening of the channel gate; either via a global transition or a sequence of local conformational changes of neighboring domains that eventually reach the channel gate.…”

Section: Discussionmentioning

confidence: 99%

Conformational Changes in the 5-HT_3A Receptor Extracellular Domain Measured by Voltage-Clamp Fluorometry

Munro

Ladefoged²,

Padmanathan

et al. 2019

Mol Pharmacol

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The 5-hydroxytryptamine (5-HT) type 3 receptor is a member of the cysteine (Cys)-loop receptor super family of ligand-gated ion channels in the nervous system and is a clinical target in a range of diseases. The 5-HT 3 receptor mediates fast serotonergic neurotransmission by undergoing a series of conformational changes initiated by ligand binding that lead to the rapid opening of an intrinsic cation-selective channel. However, despite the availability of high-resolution structures of a mouse 5-HT 3 receptor, many important aspects of the mechanistic basis of 5-HT 3 receptor function and modulation by drugs remain poorly understood. In particular, there is little direct evidence for the specific conformational changes predicted to occur during ligand-gated channel activation and desensitization. In the present study, we used voltage-clamp fluorometry (VCF) to measure conformational changes in regions surrounding the orthosteric binding site of the human 5-HT 3A (h5-HT 3A) receptor during binding of 5-HT and different classes of 5-HT 3 receptor ligands. VCF utilizes parallel measurements of receptor currents with photon emission from fluorescent reporter groups covalently attached to specific positions in the receptor structure. Reporter groups that are highly sensitive to the local molecular environment can, in real time, report conformational changes as changes in fluorescence that can be correlated with changes in receptor currents reporting the functional states of the channel. Within the loop C, D, and E regions that surround the orthosteric binding site in the h5-HT 3A receptor, we identify positions that are amenable to tagging with an environmentally sensitive reporter group that reports robust fluorescence changes upon 5-HT binding and receptor activation. We use these reporter positions to characterize the effect of ligand binding on the local structure of the orthosteric binding site by agonists, competitive antagonists, and allosterically acting channel activators. We observed that loop C appears to show distinct fluorescence changes for ligands of the same class, while loop D reports similar fluorescence changes for all ligands binding at the orthosteric site. In contrast, the loop E reporter position shows distinct changes for agonists, antagonists, and allosteric compounds, suggesting the conformational changes in this region are specific to ligand function. Interpretation of these results within the framework of current models of 5-HT 3 and Cys-loop mechanisms are used to expand the understanding of how ligand binding in Cys-loop receptors relates to channel gating. SIGNIFICANCE STATEMENT The 5-HT 3 receptor is an important ligand-gated ion channel and drug target in the central and peripheral nervous system. Determining how ligand binding induced conformational changes in the receptor is central for understanding the structural mechanisms underlying 5-HT 3 receptor function. Here, we employ voltage-gated fluorometry to characterize conformational changes in the extracellular domain of the human 5-...

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“…Combined with computational, mutational, and biochemical analysis, structures provide insight into the molecular architecture of the 5-HT 3 receptor orthosteric binding site (Kesters et al, 2013;Hassaine et al, 2014) and ligand binding modes (Joshi et al, 2006;Moura Barbosa et al, 2010;Kesters et al, 2013;Price et al, 2015Price et al, , 2016Lochner and Thompson, 2016), and the potential conformational changes associated with ligand binding (Miller and Smart, 2010;Sander et al, 2010). From this and other work, a framework is emerging for understanding the molecular basis that underlies 5-HT 3 agonism and antagonism (Nys et al, 2013;Alix et al, 2016).…”

Section: Introductionmentioning

confidence: 98%

Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT_3A Receptor

et al. 2018

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5-Hydroxytryptamine 3 (5-HT 3) receptors are ligand-gated ion channels that mediate neurotransmission by serotonin in the central nervous system. Pharmacological inhibition of 5-HT 3 receptor activity has therapeutic potential in several psychiatric diseases, including depression and anxiety. The recently approved multimodal antidepressant vortioxetine has potent inhibitory activity at 5-HT 3 receptors. Vortioxetine has an inhibitory mechanism that differs from classic 5-HT 3 receptor competitive antagonists despite being believed to bind in the same binding site. Specifically, vortioxetine shows partial agonist activity followed by persistent and insurmountable inhibition. We have investigated the binding mode of vortioxetine at the human 5-HT 3A receptor through computational and in vitro experiments to provide insight into the molecular mechanisms behind the unique pharmacological profile of the drug. We find that vortioxetine binds in a manner different from currently known 5-HT 3A orthosteric ligands. Specifically, while the binding pattern of vortioxetine mimics some aspects of both the setron class of competitive antagonists and 5-hydroxytryptamine (5-HT) with regards to interactions with residues of the aromatic box motif in the orthosteric binding site, vortioxetine also forms interactions with residues not previously described to be important for the binding of either setrons or 5-HT such as Val202 on Loop F. Our results expand the framework for understanding how orthosteric ligands drive 5-HT 3 receptor function, which is of importance for the potential future development of novel classes of 5-HT 3 receptor antagonists.

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Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT₃) Subunit A Receptors

Cited by 10 publications

References 45 publications

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

Conformational Changes in the 5-HT_3A Receptor Extracellular Domain Measured by Voltage-Clamp Fluorometry

Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT_3A Receptor

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Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT3) Subunit A Receptors

Cited by 10 publications

References 45 publications

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors

Conformational Changes in the 5-HT3A Receptor Extracellular Domain Measured by Voltage-Clamp Fluorometry

Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT3A Receptor

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Product

Resources

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Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5-Hydroxytryptamine-3 (5-HT₃) Subunit A Receptors

Conformational Changes in the 5-HT_3A Receptor Extracellular Domain Measured by Voltage-Clamp Fluorometry

Modeling and Mutational Analysis of the Binding Mode for the Multimodal Antidepressant Drug Vortioxetine to the Human 5-HT_3A Receptor