Activation of 5-hydroxytryptamine<sub>1B/1D/1F</sub>receptors as a mechanism of action of antimigraine drugs

Ramírez‐Rosas, Martha B.; Labruijere, Sieneke; Villalón, Carlos M.; VanDenBrink, Antoinette Maassen

doi:10.1517/14656566.2013.806487

Cited by 36 publications

(23 citation statements)

References 117 publications

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“…Therefore, this structural feature of the bipolarizing ergot compounds suggests they work through serotonergic blockade. This is consistent with observations that (i) structurally diverse 5-HT antagonists cause bipolarity (Table A in S1 Text ), (ii) the ergots that inhibited head regeneration act as 5-HT agonists in other systems [ 31 – 33 ], (iii) other drugs that stimulate 5-HT signaling (8-OH DPAT and fluoxetine) also block head regeneration and PZQ action [ 20 ], and (iv) RNAi of tryptophan hydroxylase (TPH) to decrease 5-HT levels potentiates PZQ action [ 20 ]. Therefore, these data show that PZQ action mimics the bipolarizing ability of serotonergic blockers, and is opposed by 5-HT agonists.…”

Section: Resultssupporting

confidence: 90%

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

et al. 2015

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Praziquantel (PZQ) is a key therapy for treatment of parasitic flatworm infections of humans and livestock, but the mechanism of action of this drug is unresolved. Resolving PZQ-engaged targets and effectors is important for identifying new druggable pathways that may yield novel antiparasitic agents. Here we use functional, genetic and pharmacological approaches to reveal that serotonergic signals antagonize PZQ action in vivo. Exogenous 5-hydroxytryptamine (5-HT) rescued PZQ-evoked polarity and mobility defects in free-living planarian flatworms. In contrast, knockdown of a prevalently expressed planarian 5-HT receptor potentiated or phenocopied PZQ action in different functional assays. Subsequent screening of serotonergic ligands revealed that several ergot alkaloids possessed broad efficacy at modulating regenerative outcomes and the mobility of both free living and parasitic flatworms. Ergot alkaloids that phenocopied PZQ in regenerative assays to cause bipolar regeneration exhibited structural modifications consistent with serotonergic blockade. These data suggest that serotonergic activation blocks PZQ action in vivo, while serotonergic antagonists phenocopy PZQ action. Importantly these studies identify the ergot alkaloid scaffold as a promising structural framework for designing potent agents targeting parasitic bioaminergic G protein coupled receptors.

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Section: Resultssupporting

confidence: 90%

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

et al. 2015

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“…The ergolines as a class of drugs, in general, are recognized as having several receptor targets including but not limited to 5-HT 1A-1F , 5-HT 2A-C , D 1-5 , as well as α1 and α2 adrenergic receptor types (Silberstein, 1997). The antimigraine effects, however, are likely mediated through agonist activity at the 5-HT 1B , 5-HT 1D and possibly 5-HT 1F receptors present on trigeminal nerve terminals (Ramirez Rosas et al, 2013). However, ergotamine as well as other antimigraine ergolines, such as dihydroergotamine and methysergide, suffer from acute side-effects due to vasoconstriction in the periphery leading to hypertension and coronary vasoconstriction.…”

Section: Historic Aspects and Significancementioning

confidence: 99%

Structure and function of serotonin G protein-coupled receptors

McCorvy

Roth

2015

Pharmacology & Therapeutics

288

252

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Serotonin receptors are prevalent throughout the nervous system and the periphery, and remain one of the most lucrative and promising drug discovery targets for disorders ranging from migraine headaches to neuropsychiatric disorders such as schizophrenia and depression. There are 14 distinct serotonin receptors, of which 13 are G protein coupled receptors (GPCRs), which are targets for approximately 40% of the approved medicines. Recent crystallographic and biochemical evidence has provided a converging understanding of the basic structure and functional mechanics of GPCR activation. Currently, two GPCR crystal structures exist for the serotonin family, the 5-HT1B and 5-HT2B receptor, with the antimigraine and valvulopathic drug ergotamine bound. The first serotonin crystal structures not only provide the first evidence of serotonin receptor topography but also provide mechanistic explanations into functional selectivity or biased agonism. This review will detail the findings of these crystal structures from a molecular and mutagenesis perspective for driving rational drug design for novel therapeutics incorporating biased signaling.

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“…Hypersensitization of the brainstem trigeminal sensory complex may underlie the primary brain dysfunction in migraine [1; 10; 58; 71], leading to brainstem-mediated upregulation of cortical excitability [14; 40]. Therapeutic options have targeted brainstem neuromodulatory centers, including serotonergic (raphe nuclei) and noradrenergic (locus coeruleus) nuclei [19; 63], via dihydroergotamine, triptans, and other 5HT1B/1D agonists [21; 41; 62]. More recently, novel neuromodulation therapies have been proposed [44; 65].…”

Section: Introductionmentioning

confidence: 99%

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients

García

Lin

Lee

et al. 2017

Pain

107

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Migraine pathophysiology includes altered brainstem excitability, and recent neuromodulatory approaches aimed at controlling migraine episodes have targeted key brainstem relay and modulatory nuclei. In this study, we evaluated the impact of respiratory-gated auricular vagal afferent nerve stimulation (RAVANS), a novel neuromodulatory intervention based on an existing transcutaneous Vagus Nerve Stimulation approach, in the modulation of brainstem activity and connectivity in migraine patients. We applied 3T-functional magnetic resonance imaging with improved in-plane spatial resolution (2.62×2.62 mm) in episodic migraine (interictal) and age- and sex-matched healthy controls to evaluate brain response to RAVANS (gated to either inhalation or exhalation) and sham stimulation. We further investigated RAVANS modulation of tactile trigeminal sensory afference response in the brainstem using air-puff stimulation directed to the forehead during functional magnetic resonance imaging. Compared to sham and inhalatory-gated RAVANS (iRAVANS), exhalatory-gated RAVANS (eRAVANS) activated an ipsilateral pontomedullary region consistent with nucleus tractus solitarii (NTS). During eRAVANS, NTS connectivity was increased to anterior insula and anterior mid-cingulate cortex, compared to both sham and iRAVANS, in migraine patients. Increased connectivity was inversely correlated with relative time to the next migraine attack, suggesting clinical relevance to this change in connectivity. Post-stimulation effects were also noted immediately following eRAVANS, as we found increased activation in putative pontine serotonergic (i.e. nucleus raphe centralis) and noradrenergic (i.e. locus coeruleus) nuclei in response to trigeminal sensory afference. Regulation of activity and connectivity of brainstem and cortical regions involved in serotonergic and noradrenergic regulation and pain modulation may constitute an underlying mechanism supporting beneficial clinical outcomes for eRAVANS applied for episodic migraine.

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Activation of 5-hydroxytryptamine_1B/1D/1Freceptors as a mechanism of action of antimigraine drugs

Cited by 36 publications

References 117 publications

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

Structure and function of serotonin G protein-coupled receptors

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients

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Activation of 5-hydroxytryptamine1B/1D/1Freceptors as a mechanism of action of antimigraine drugs

Cited by 36 publications

References 117 publications

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

Ergot Alkaloids (Re)generate New Leads as Antiparasitics

Structure and function of serotonin G protein-coupled receptors

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients

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Activation of 5-hydroxytryptamine_1B/1D/1Freceptors as a mechanism of action of antimigraine drugs