Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1

Díaz-Franulic, Ignacio; Cáceres-Molina, Javier; Sepúlveda, Romina V.; González‐Nilo, Fernando; Latorre, Ramón

doi:10.1124/mol.116.104430

Cited by 18 publications

(20 citation statements)

References 113 publications

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“…These relationships are fully described in Table II and include a protonation site (R491) [45], capsaicin interacting sites and residues that contribute to the hydrophobic interior of transmembranes domains S1,2, and 4 [60]. Several are involved in voltage or thermal sensing [61,62], and based on mutagenesis studies this Myrcene binding site might also be sensitive to Resiniferatoxin competition [62][63][64]. Residues close to the S4-S5 linker, a key regulatory region for TRPs, are also implicated in binding.…”

Section: Internal Calcium Impact On Myrcene Activation Of Trpv1mentioning

confidence: 99%

Myrcene and terpene regulation of TRPV1

et al. 2019

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Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization. Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1. We used inducible expression of TRPV1 to examine TRPV1-dependency of terpene-induced calcium flux responses. Terpenes contribute differentially to calcium fluxes via TRPV1 induced by Cannabis-mimetic cannabinoid/terpenoid mixtures. Myrcene dominates the TRPV1-mediated calcium responses seen with terpenoid mixtures. Myrcene-induced calcium influx is inhibited by the TRPV1 inhibitor capsazepine and Myrcene elicits TRPV1 currents in the wholecell patch-clamp configuration. TRPV1 currents are highly sensitive to internal calcium. When Myrcene currents are evoked, they are distinct from capsaicin responses on the basis of I max and their lack of shift to a pore-dilated state. Myrcene pre-application and residency at TRPV1 appears to negatively impact subsequent responses to TRPV1 ligands such as Cannabidiol, indicating allosteric modulation and possible competition by Myrcene. Molecular docking studies suggest a non-covalent interaction site for Myrcene in TRPV1 and identifies key residues that form partially overlapping Myrcene and Cannabidiol binding sites. We identify several non-Cannabis plantderived sources of Myrcene and other compounds targeting nociceptive TRPs using a data mining approach focused on analgesics suggested by non-Western Traditional Medical Systems. These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.

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Section: Internal Calcium Impact On Myrcene Activation Of Trpv1mentioning

confidence: 99%

Myrcene and terpene regulation of TRPV1

et al. 2019

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“…We further report that both hypothermia‐inducing TRPV1 antagonists studied (A‐1165901 and AMG7905) potently potentiate the activation of TRPV1 channels by protons in vitro, while potently blocking the capsaicin mode. In view of the pharmacological complexity of TRPV1, it is important to note that neither AMG7905 nor A‐1165901 shows any agonistic activity (ie does not activate the TRPV1 channel by itself, in the absence of any agonists). These new data are in line with the report by Lehto et al who first observed that AMG7905 and AMG8562 potentiated TRPV1 activation by protons in vitro and proposed that such potentiation correlated with the ability of a TRPV1 antagonist to cause hypothermia.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the hypothermic side effect of TRPV1 antagonists introduces a new concern for drug development. The known hyperthermic side effect is widely acknowledged as a major problem for the development of TRPV1 antagonists . Does the hypothermic effect, with its unknown mechanisms, represent another major problem?…”

Section: Introductionmentioning

confidence: 99%

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

et al. 2018

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AimThermoregulatory side effects hinder the development of transient receptor potential vanilloid‐1 (TRPV1) antagonists as new painkillers. While many antagonists cause hyperthermia, a well‐studied effect, some cause hypothermia. The mechanisms of this hypothermia are unknown and were studied herein.MethodsTwo hypothermia‐inducing TRPV1 antagonists, the newly synthesized A‐1165901 and the known AMG7905, were used in physiological experiments in rats and mice. Their pharmacological profiles against rat TRPV1 were studied in vitro.ResultsAdministered peripherally, A‐1165901 caused hypothermia in rats by either triggering tail‐skin vasodilation (at thermoneutrality) or inhibiting thermogenesis (in the cold). A‐1165901‐induced hypothermia did not occur in rats with desensitized (by an intraperitoneal dose of the TRPV1 agonist resiniferatoxin) sensory abdominal nerves. The hypothermic responses to A‐1165901 and AMG7905 (administered intragastrically or intraperitoneally) were absent in Trpv1 −/− mice, even though both compounds evoked pronounced hypothermia in Trpv1 +/+ mice. In vitro, both A‐1165901 and AMG7905 potently potentiated TRPV1 activation by protons, while potently blocking channel activation by capsaicin.Conclusion TRPV1 antagonists cause hypothermia by an on‐target action: on TRPV1 channels on abdominal sensory nerves. These channels are tonically activated by protons and drive the reflectory inhibition of thermogenesis and tail‐skin vasoconstriction. Those TRPV1 antagonists that cause hypothermia further inhibit these cold defences, thus decreasing body temperature.SignificanceTRPV1 antagonists (of capsaicin activation) are highly unusual in that they can cause both hyper‐ and hypothermia by modulating the same mechanism. For drug development, this means that both side effects can be dealt with simultaneously, by minimizing these compounds’ interference with TRPV1 activation by protons.

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“…[17][18][19] Given that TRPA1 and TRPV1 receptors appear to have allosteric sites, it is possible that entourage effects are mediated by terpenoid allosteric modulation of cannabinoid actions at these receptors. [20][21][22] In the present study we aimed to assess whether seven terpenoids most commonly found in cannabis have activity at TRPV1 and TRPA1 channels alone, as well as observing whether they modulate the effects of phytocannabinoids and endocannabinoids on these receptors.…”

Section: Introductionmentioning

confidence: 99%

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels

Heblinski

Santiago

Fletcher

et al. 2020

Cannabis and Cannabinoid Research

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Introduction: Cannabis sativa produces hundreds of bioactive compounds, including cannabinoids and terpenoids. It has been proposed that cannabinoids act in synergy with terpenoids to produce the entourage effect, a concept used to explain the therapeutic benefits of medicinal cannabis. One molecular explanation for the entourage effect is that the terpenoids augment the actions of cannabinoids at their molecular drug targets in cells. We recently reported that terpenoids commonly found in cannabis do not influence the functional effects of D 9 -tetrahydrocannabinol (D 9 -THC) on cannabinoid 1 and cannabinoid 2 receptors. The present study aimed to extend on this research by examining whether terpenoids influence the effects of phytocannabinoids and endocannabinoids on human transient receptor potential ankyrin 1 (hTRPA1) and human transient receptor potential vanilloid 1 (hTRPV1) channels heterologously expressed in mammalian cells. Materials and Methods: The activity of terpenoids, phytocannabinoids, and endocannabinoids was assessed in inducible HEK Flp-In T-Rex cells transfected with hTRPA1 and hTRPV1 channels, respectively. Real-time changes in intracellular calcium ([Ca] i ) were measured using the Calcium 5 dye and a FlexStation 3 plate reader. Results: a-pinene, b-pinene, b-caryophyllene, linalool, limonene, b-myrcene or a-humulene did not affect [Ca] i in hTRPA1 and hTRPV1 overexpressing cells. Cinnamaldehyde (CA), D 9 -THC, and 2-arachidonoylglycerol (2-AG) activated TRPA1 receptors with high efficacy and similar potency (EC 50 s of *10 lM). Capsaicin and anandamide (AEA) activated TRPV1 receptors with an EC 50 of 61 nM and 4.3 lM, respectively, but TRPV1 showed no response to D 9 -THC, cannabidiol, and other minor cannabinoids. Terpenoids did not significantly affect the responses of TRPA1 and TRPV1 receptors to submaximal and maximal concentrations of CA and D 9 -THC or the endocannabinoids AEA and 2-AG. Discussion: We could not find any evidence that the terpenoids tested here activate TRPA1 and TRPV1 channels or modulate their activation by D 9 -THC and other agonists, including endocannabinoids.

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Structure-Driven Pharmacology of Transient Receptor Potential Channel Vanilloid 1

Cited by 18 publications

References 113 publications

Myrcene and terpene regulation of TRPV1

Myrcene and terpene regulation of TRPV1

TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in rodents: Compounds’ pharmacological profiles, in vivo targets, thermoeffectors recruited and implications for drug development

Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Actions of Phytocannabinoids or Endocannabinoids on TRPA1 and TRPV1 Channels

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