Discovery of dual-acting opioid ligand and TRPV1 antagonists as novel therapeutic agents for pain

Lee, Hobin; Ahn, Songyeon; Ann, Jihyae; Ha, Hee-Jin; Yoo, Youngdong; Kim, Young Ho; Hwang, Ji-Young; Jang, Choon‐Gon; Jang, Choon‐Gon; Pearce, Larry V.; Esch, Timothy E.; Lewin, Nancy E.; Blumberg, Peter M.; Lee, Jeeyeon

doi:10.1016/j.ejmech.2019.111634

Cited by 27 publications

(21 citation statements)

References 17 publications

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“…Capsaicin is a lipophilic molecule that binds to the transmembrane domain of TRPV1, presumably aided by local lipid interactions provided by the membrane environment (Cao et al, 2013a,b;Hanson et al, 2015). The capsaicin receptor TRPV1 serves as a critical node in nociception, representing an attractive target for modifying pain sensations (Basso et al, 2019;Lee et al, 2019). Thus, further research into the TRPV1 channel would enhance our understanding of the thresholds or dynamic range of pain sensation and perhaps reveal potential therapeutic applications.…”

Section: Discussionmentioning

confidence: 99%

Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli

Liu

Chen

Mei

et al. 2020

Front. Mol. Neurosci.

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The tetrameric capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) in mammals has evolved the capability to integrate pain signal arising from harmful temperature and chemical irritants. The four repetitions of TRPV1 subunits result in an ion channel with excellent pain sensitivity, allowing this ionotropic receptor to differentiate graded injuries. We manipulated the stoichiometry and relative steric coordination of capsaicin-bound structures at the molecular level to determine the rules by which the receptor codes pain across a broad range of intensities. By introducing capsaicin-insensitive S512F mutant subunits into the TRPV1 channel, we found that binding of the first ligand results in low but clear channel activation. Maximal agonist-induced activation is already apparent in tetramers harboring two or three wild-type TRPV1 subunits, which display comparable activity to wild-type tetramer. The non-vanilloid agonist 2-aminoethoxydiphenyl borate (2-APB) differs from that of capsaicin in the TRPV1 channel opening mechanism activating all S512F-mutated TRPV1 channels. Two or more wild-type TRPV1 subunits are also required for full anandamide-induced channel activation, a cannabinoid that shares overlapping bindingpocket to capsaicin. Our results demonstrate that the stoichiometry of TRPV1 activation is conserved for two types of agonists.

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Section: Discussionmentioning

confidence: 99%

Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli

Liu

Chen

Mei

et al. 2020

Front. Mol. Neurosci.

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“…> 50% at 633 nm, T = 25 • C). The results were also expressed as intensity Distribution (Di), i.e., the size below which is placed the 10% [Di (10)], 50% [Di(50)], and 90% [Di(90)] of all the particles.…”

Section: Particle Size Distributionmentioning

confidence: 99%

“…In the brain, TRPV1 receptors are also involved in the modulation of synaptic plasticity as well as in epilepsy and cognition [7]. Within the peripheral nervous system, the TRPV1 receptors are located in sensory ganglia and in small sensory C and Aδ fibers [5,8], thus representing a promising target for the modulation of pain sensitivity [9,10]. In this context, the upor down-regulation of TRPV1 receptors has been shown.…”

Section: Introductionmentioning

confidence: 99%

Lipid Nanoparticle Inclusion Prevents Capsaicin-Induced TRPV1 Defunctionalization

et al. 2020

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Background: Capsaicin (CPS) is a highly selective agonist of the transient receptor potential vanilloid type 1 (TRPV1) with a nanomolar affinity. High doses or prolonged exposure to CPS induces TRPV1 defunctionalization and, although this effect is currently used for the treatment of thermal hyperalgesia in chronic pain conditions, it is responsible of detrimental effects, such as denervation of sensory fibers. The aim of the present study was to formulate CPS loaded lipid nanocarriers (CPS-LN) in order to optimize CPS release, thus preventing TRPV1 internalization and degradation. Methods: CPS-LNs were formulated and characterized by in vitro studies. The activation of TRPV1 receptors after CPS-LN administration was evaluated by measuring spontaneous pain that was induced by local injection into the plantar surface of the mouse hind-paw. Moreover, the expression of TRPV1 in the skin was evaluated by western blot analysis in CPS-LN injected mice and then compared to a standard CPS solution (CPS-STD). Results: CPS inclusion in LN induced a lower pain response when compared to CPS-STD; further, it prevented TRPV1 down-regulation in the skin, while CPS-STD induced a significant reduction of TRPV1 expression. Conclusions: Drug encapsulation in lipid nanoparticles produced an optimization of CPS release, thus reducing mice pain behavior and avoiding the effects that are caused by TRPV1 defunctionalization related to a prolonged activation of this receptor.

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“…This test was performed with minor modifications to the previously reported method [18]. membrane in binding buffer (50 mM Hepes, 5 mM MgCl2, 1 mM CaCl2, and 0.2% BSA) for 2 h. The mixture was then transferred to a GF/C 96-well filter plate coated with 0.33% polyethyleneimine.…”

Section: In Vitro Cb1r-binding Assaymentioning

confidence: 99%

QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids

Lee

Park

Hwang

et al. 2020

Preprint

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In recent years, there have been frequent reports on the adverse effects of synthetic cannabinoid (SC) abuse. SCs cause psychoactive effects, similar to those caused by marijuana, by binding and activating cannabinoid receptor 1 (CB1R) in the central nervous system. The aim of this study was to establish a reliable quantitative structure-activity relationship (QSAR) model to correlate the structures and physicochemical properties of various SCs with their CB1R-binding affinities. We prepared 15 SCs and their derivatives (tetrahydrocannabinol [THC], naphthoylindoles, and cyclohexylphenols) and determined their binding affinity to CB1R, which is known as a dependence-related target. We calculated the molecular descriptors for dataset compounds using an R/CDK (R package integrated with CDK, version 3.5.0) toolkit to build QSAR regression models. These models were established and statistical evaluations were performed using the mlr and plsr packages in R software. The most reliable QSAR model was obtained from the partial least squares regression method via external validation. This model can be applied in vivo to predict the addictive properties of illicit new SCs. Using a limited number of dataset compounds and our own experimental activity data, we built a QSAR model for SCs with good predictability. This QSAR modeling approach provides a novel strategy for establishing an efficient tool to predict the abuse potential of various SCs and to control their illicit use.

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Discovery of dual-acting opioid ligand and TRPV1 antagonists as novel therapeutic agents for pain

Cited by 27 publications

References 17 publications

Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli

Two Vanilloid Ligand Bindings Per Channel Are Required to Transduce Capsaicin-Activating Stimuli

Lipid Nanoparticle Inclusion Prevents Capsaicin-Induced TRPV1 Defunctionalization

QSAR Model for Predicting the Cannabinoid Receptor 1 Binding Affinity and Dependence Potential of Synthetic Cannabinoids

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