Analysis of structure–activity relationships for the ‘B-region’ of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]-thiourea analogues as TRPV1 antagonists

Lee, Jeeyeon; Jin, Michelle; Kang, Sang-Uk; Kim, Su Yeon; Lee, Jiyoun; Shin, Moon Sam; Hwang, Jaemin; Cho, Sookhyun; Choi, Yun-Hyuk; Choi, Ho Jin; Kim, Sang Hoon; Suh, Young‐Ger; Lee, Yong‐Sil; Kim, Young‐Ho; Ha, Hee-Jin; Tóth, Attila; Pearce, Larry V.; Tran, Richard; Szabó, Tamás; Welter, Jacqueline D.; Lundberg, Daniel J.; Wang, Yun; Lázár, József; Pavlyukovets, Vladimir A.; Morgan, Matthew A.; Blumberg, Peter M.

doi:10.1016/j.bmcl.2005.06.006

Cited by 13 publications

(11 citation statements)

References 28 publications

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“…Isocyanate 23 was synthesized accordingly to a reported procedure, starting from tert -butyl (4-(aminomethyl)phenyl)carbamate, which in turn was prepared as in ref . Isocyanate 34 was synthesized according to a previously reported procedure …”

Section: Methodsmentioning

confidence: 99%

New β-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins

et al. 2016

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A novel series of β-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing αβ, αβ, αβ, αβ, αβ, αβ, and αβ integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by αβ, αβ, αβ, or αβ integrin, and antagonists for the integrins αβ and αβ as well as αβ and αβ, preventing the effects elicited by the respective endogenous agonists.

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Section: Methodsmentioning

confidence: 99%

New β-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins

et al. 2016

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“…Furthermore, mutagenesis studies within the TM3/4 region identified several key molecular determinants such as Tyr 511 , Ser 512 ,Met/Leu 547 , and Thr 550 that led to the proposed models of agonist and antagonist interactions with the vanilloidbinding pocket (Jordt and Julius, 2002;Chou et al, 2004;Gavva et al, 2004;Lee et al, 2005). Molecular determinants for proton activation have been reported to be present in the prepore loop, such as Glu 600 and Glu 648 (Jordt et al, 2000) and are different from those that constitute the vanilloidbinding pocket.…”

mentioning

confidence: 99%

A Polyclonal Antibody to the Prepore Loop of Transient Receptor Potential Vanilloid Type 1 Blocks Channel Activation

Klionsky

Tamir²,

Holzinger³

et al. 2006

J Pharmacol Exp Ther

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Transient receptor potential vanilloid type 1 (TRPV1) can be activated by multiple chemical and physical stimuli such as capsaicin, anandamide, protons, and heat. Capsaicin interacts with the binding pocket constituted by transmembrane regions 3 and 4, whereas protons act through residues in the prepore loop of TRPV1. Here, we report on characterization of polyclonal and monoclonal antibodies to the prepore loop of TRPV1. A rabbit anti-rat TRPV1 polyclonal antibody (Ab-156H) acted as a full antagonist of proton activation (IC 50 values for pH 5 and 5.5 were 364.68 Ϯ 29.78 and 28.31 Ϯ 6.30 nM, respectively) and as a partial antagonist of capsaicin, heat, and pH 6 potentiated chemical ligand (anandamide and capsaicin) activation (50 -79% inhibition). Ab-156H antagonism of TRPV1 is not affected by the conformation of the capsaicin-binding pocket because it is equally potent at wild-type (capsaicinsensitive) rat TRPV1 and its T550I mutant (capsaicin-insensitive). With the goal of generating monoclonal antagonist antibodies to the prepore region of human TRPV1, we used a recently developed rabbit immunization protocol. Although rabbit polyclonal antiserum blocked human TRPV1 activation, rabbit monoclonal antibodies (identified on the basis of selective binding to Chinese hamster ovary cells expressing human TRPV1) did not block activation by either capsaicin or protons. Thus, rabbit polyclonal antibodies against rat and human TRPV1 prepore region seem to partially lock or stabilize the channel in the closed state, whereas rabbit anti-human TRPV1 monoclonal antibodies bind to the prepore region but do not lock or stabilize the channel conformation.Transient receptor potential vanilloid type 1 (VR1 or TRPV1), a nonselective cation channel, is activated by chemical ligands (capsaicin, anandamide, and protons, pH Յ 5.7) and heat (Ͼ42°C), acting as an integrator of multiple noxious stimuli (Caterina et al

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“…As the model of Gavva et al is consistent with these observations, we adopted this structural model for the docking and visualization of some representative cinnamides reported here, with the purpose of showing plausible interactions of the antagonists with the TM3/4 helices, consistent with the 3D-QSAR models proposed here. The model was generated by building the TM3 and TM4 helical protein segments in α-helical conformation, with a loop connecting the helices, using the Biopolymer module of Insight II . This structural model 3 was also employed by Lee et al for docking and analyzing a different class of the TRPV1 antagonists, similar in size to the current set of ligands.…”

Section: Resultsmentioning

confidence: 99%

Three-Dimensional Quantitative Structure−Activity Relationships and Activity Predictions of Human TRPV1 Channel Antagonists: Comparative Molecular Field Analysis and Comparative Molecular Similarity Index Analysis of Cinnamides

2007

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3D-QSAR models for human TRPV1 channel antagonists were developed based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), using a training set of 61 cinnamide TRPV1 antagonists and tested on an independent test set of 47 antagonists. Molecular alignment procedure included weights for both internal energy and atom-to-atom matching against a reference or probe. Sensitivity of results on partial charge assignments was explored using multiple charge sets. AM1-BCC charge assignments gave better results for both CoMFA and CoMSIA models. For the best CoMFA model, the statistics are, r2 = 0.96, q2 = 0.58, n = 61 for the training set and r2 = 0.50, n = 47 for the test set. For the best CoMSIA model, the statistics are r2 = 0.95, q2 = 0.57, n = 61 for the training set and r2 = 0.48, n = 47 for the test set. These models are consistent with the proposed binding modes and interactions of known activators of the TRPV1 channel such as capsaicin, in a structural model of the TM3/4 helical region of TRPV1.

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Analysis of structure–activity relationships for the ‘B-region’ of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]-thiourea analogues as TRPV1 antagonists

Abstract: The structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. A docking model of potent antagonist 2 with the sensor region of TRPV1 is proposed.

Cited by 13 publications

References 28 publications

New β-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins

New β-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins

A Polyclonal Antibody to the Prepore Loop of Transient Receptor Potential Vanilloid Type 1 Blocks Channel Activation

Three-Dimensional Quantitative Structure−Activity Relationships and Activity Predictions of Human TRPV1 Channel Antagonists: Comparative Molecular Field Analysis and Comparative Molecular Similarity Index Analysis of Cinnamides

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