Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands

Kim, Myeong Seop; Ki, Yooran; Ahn, Song Yeon; Yoon, Suyoung; Kim, Sung Eun; Park, Hyeung Geun; Sun, Wei; Son, Karam; Cui, Minghua; Choi, Sun; Pearce, Larry V.; Esch, Timothy E.; DeAndrea-Lazarus, Ian A; Blumberg, Peter M.; Lee, Jeeyeon

doi:10.1016/j.bmcl.2013.10.064

Cited by 11 publications

(11 citation statements)

References 18 publications

(7 reference statements)

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“…All these results were congruent with the reports [10, 23, 24, 40] that the identified critical hydrophilic and hydrophobic residues, including Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670, were important for compound recognition by TRPV1. Among them, Tyr511, Thr550, Asn551, and Arg557 formed hydrogen bonds with the ligands, while Leu518, Leu547, and Leu670 interacted with the ligands with hydrophobic interactions.…”

Section: Resultssupporting

confidence: 92%

“…Transient receptor potential vanilloid 1 (TRPV1) [10–14], a heat-sensitive and nonselective calcium-permeable cation channel of the TRP channel super-family, is a hub in the neuronal inflammatory signaling pathway network. TRPV1 has been reported to possess pro-inflammatory and nociceptive properties in the peripheral nervous system (PNS) and to contribute to acute and chronic pain [15], such as in osteoarthritis, neuropathic pain, migraine, inflammatory bowel disease, and bone cancer [16].…”

Section: Introductionmentioning

confidence: 99%

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Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Feng

Pearce

Zhang

et al. 2016

AAPS J

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Transient receptor potential vanilloid type 1 (TRPV1), a heat-sensitive calcium channel protein, contributes to inflammation as well as to acute and persistent pain. Since TRPV1 occupies a central position in pathways of neuronal inflammatory signaling, it represents a highly attractive potential therapeutic target for neuroinflammation. In the present work, we have in silico identified a series of diarylurea analogues for hTRPV1, of which 11 compounds showed activity in the nanomolar to micromolar range as validated by in vitro biological assays. Then, we utilized molecular docking to explore the detailed interactions between TRPV1 and the compounds to understand the contributions of the different substituent groups. Tyr511, Leu518, Leu547, Thr550, Asn551, Arg557, and Leu670 were important for the recognition of the small molecules by TRPV1. A hydrophobic group in R2 or a polar/hydrophilic group in R1 contributed significantly to the activities of the antagonists at TRPV1. In addition, the subtle different binding pose of meta-chloro in place of para-fluoro in the R2 group converted antagonism into partial agonism, as was predicted by our short-term molecular dynamics (MD) simulation and validated by bioassay. Importantly, compound 15, one of our best TRPV1 inhibitors, also showed potential binding affinity (1.39 µM) at cannabinoid receptor 2 (CB2), which is another attractive target for immune-inflammation diseases. Furthermore, compound 1 and its diarylurea analogues were predicted to target the C-X-C chemokine receptor 2 (CXCR2), although bioassay validation of CXCR2 with these compounds still needs to be performed. This prediction from the modeling is of interest, since CXCR2 is also a potential therapeutic target for chronic inflammatory diseases. Our findings provide novel strategies to develop a small molecule inhibitor to simultaneously target two or more inflammation-related proteins for the treatment of a wide range of inflammatory disorders including neuroinflammation and neurodegenerative diseases with potential synergistic effect.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Feng

Pearce

Zhang

et al. 2016

AAPS J

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“…The detailed interactions between hTRPV1/rTRPV1 and their ligands cannot therefore be ascertained with certainty, although there has been substantial work using modeled structures. 21–24 Of particular interest are the differences between TRPV1 bound with agonists and with antagonists.…”

Section: Introductionmentioning

confidence: 99%

Structural Insight into Tetrameric hTRPV1 from Homology Modeling, Molecular Docking, Molecular Dynamics Simulation, Virtual Screening, and Bioassay Validations

Feng¹,

Pearce

Xu³

et al. 2015

J. Chem. Inf. Model.

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The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

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“…The synthesized amines (6,8,11,15,19) were coupled with propionic acid [20] as previously reported to afford the final compounds 20e46 (Scheme 4).…”

Section: Chemistrymentioning

confidence: 99%

“…In view of the potential of TRPV1 as a therapeutic target, intense effort by many groups has been directed at the development of potent TRPV1 antagonists [9e17] and at understanding of the structural basis for potent ligand binding [18]. We have used the ultrapotent TRPV1 ligand resiniferatoxin as a structural lead for antagonist development [19].…”

Section: Introductionmentioning

confidence: 99%

Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

Ryu

Seo

Lee

et al. 2015

European Journal of Medicinal Chemistry

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A series of pyridine derivatives in the C-region of N-((6-trifluoromethyl-pyridin-3-yl)methyl) 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides were investigated as hTRPV1 antagonists. The SAR analysis indicated that 6-difluorochloromethyl pyridine derivatives were the best surrogates of the C-region for previous leads. Among them, compound 31 showed excellent antagonism to capsaicin as well as to multiple hTRPV1 activators. It demonstrated strong analgesic activity in the formalin test in mice with full efficacy and it blocked capsaicin-induced hypothermia in vivo.

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Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands

Cited by 11 publications

References 18 publications

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation

Structural Insight into Tetrameric hTRPV1 from Homology Modeling, Molecular Docking, Molecular Dynamics Simulation, Virtual Screening, and Bioassay Validations

Pyridine C-region analogs of 2-(3-fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists

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