Identification of Indole Alkaloid Structural Units Important for Stimulus-Selective TRPM8 Inhibition: SAR Study of Naturally Occurring Iboga Derivatives

Terada, Yuko; Kitajima, Mariko; Taguchi, Fuyumi; Takayama, Hiromitsu; Horie, Syunji; Watanabe, Tatsuo

doi:10.1021/np500235b

Cited by 36 publications

(24 citation statements)

References 23 publications

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“…Based on the existing structural information on the modulation of TRPM8 [93,138], Gomez-Monterrey's group designed a series of tryptamine-based derivatives, including indole ring decoration at the N-1, 3, and 5 positions [139]. Data from fluorescence assays, using 0.5, 5, and 50 µM concentrations of synthesized compounds, allowed the identification of derivative 17 (Figure 4) as an agonist of the TRPM8 channels, while related analogues behave as antagonists (see antagonists' section).…”

Section: Trpm8 Agonistsmentioning

confidence: 99%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.

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Section: Trpm8 Agonistsmentioning

confidence: 99%

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Izquierdo

Martı́n-Martı́nez

Gómez-Monterrey

et al. 2021

IJMS

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“…Indole alkaloids are produced by plants using a series of unique biosynthetic pathways, leading to an impressive diversity of complex natural products . Many indole alkaloids are endowed with significant biological activities important to human health and the treatment of disease (Scheme ) . The indole alkaloids vincristine ( 88 ) and vinblastine ( 70 ) were discovered in Catharanthus roseus (Madagascar periwinkle) and have had a remarkable impact on cancer therapies over the past several decades .…”

Section: Indole Alkaloid Natural Products and Indole‐based Small Molementioning

confidence: 99%

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

Norwood

Huigens

2019

ChemBioChem

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Indole‐containing compounds demonstrate an array of biological activities relevant to numerous human diseases. The biological activities of diverse indole‐based agents are driven by molecular interactions between indole agent and critical therapeutic target. The chemical inventory of medicinally useful or promising indole compounds spans the entire structural spectrum, from simple synthetic indoles to highly complex indole alkaloids. In an analogous fashion, the chemistry behind the indole heterocycle is unique and provides rich opportunities for extensive synthetic chemistry, enabling the construction and development of novel indole compounds to explore chemical space. This review will present heterocyclic chemistry of the indole nucleus, indole compounds of clinical use, complex indole alkaloids and indole‐inspired discovery efforts by multiple research groups interested in using novel indole‐containing small molecules to drive discoveries in human biology and medicine.

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“…In addition to modulating serotoninergic binding pockets of GPCRs, tryptaminergic ligands also modulate the activity of TRPM8 [ 42 ], a channel notorious for activation by broad chemotypes. Tryptaminergic ligands of TRPM8 include 5-benzyloxytryptamine [ 43 , 44 ], certain N-substituted tryptamines [ 45 ] and indole alkaloids [ 46 ].…”

Section: Host Target(s) Of ±Pzqmentioning

confidence: 99%

Activation of host transient receptor potential (TRP) channels by praziquantel stereoisomers

et al. 2018

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The anthelmintic praziquantel (±PZQ) serves as a highly effective antischistosomal therapy. ±PZQ causes a rapid paralysis of adult schistosome worms and deleterious effects on the worm tegument. In addition to these activities against the parasite, ±PZQ also modulates host vascular tone in blood vessels where the adult worms reside. In resting mesenteric arteries ±PZQ causes a constriction of basal tone, an effect mediated by (R)-PZQ activation of endogenous serotoninergic G protein coupled receptors (GPCRs). Here, we demonstrate a novel vasodilatory action of ±PZQ in mesenteric vessels that are precontracted by high potassium-evoked depolarization, an effect previously reported to be associated with agonists of the transient receptor potential melastatin 8 channel (TRPM8). Pharmacological profiling a panel of 17 human TRPs demonstrated ±PZQ activity against a subset of human TRP channels. Several host TRP channels (hTRPA1, hTRPC3, hTRPC7) were activated by both (R)-PZQ and (S)-PZQ over a micromolar range whereas hTRPM8 showed stereoselective activation by (S)-PZQ. The relaxant effect of ±PZQ in mesenteric arteries was caused by (S)-PZQ, and mimicked by TRPM8 agonists. However, persistence of both (S)-PZQ and TRPM8 agonist evoked vessel relaxation in TRPM8 knockout tissue suggested that canonical TRPM8 does not mediate this (S)-PZQ effect. We conclude that (S)-PZQ is vasoactive over the micromolar range in mesenteric arteries although the molecular mediators of this effect remain to be identified. These data expand our knowledge of the polypharmacology and host vascular efficacy of this clinically important anthelmintic.

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Identification of Indole Alkaloid Structural Units Important for Stimulus-Selective TRPM8 Inhibition: SAR Study of Naturally Occurring Iboga Derivatives

Cited by 36 publications

References 23 publications

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

Activation of host transient receptor potential (TRP) channels by praziquantel stereoisomers

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