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1.

001-es BibID:BIBFORM020696
Első szerző:Choi, Hyun-Kyung
Cím:Non-vanillyl resiniferatoxin analogues as potent and metabolically stable transient receptor potential vanilloid 1 agonists / Choi Hyun-Kyung, Choi Sun, Lee Yoonji, Kang Dong Wook, Ryu HyungChul, Maeng Han-Joo, Chung Suk-Jae, Pavlyukovets Vladimir A., Pearce Larry V., Toth Attila, Tran Richard, Wang Yun, Morgan Matthew A., Blumberg Peter M., Lee Jeewoo
Dátum:2009
ISSN:0968-0896
Megjegyzések:A series of non-vanillyl resiniferatoxin analogues, having 4-methylsulfonylaminophenyl and fluorophenyl moieties as vanillyl surrogates, have been investigated as ligands for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Although lacking the metabolically problematic 4-hydroxy substituent on the A-region phenyl ring, the compounds retained substantial agonist potency. Indeed, the 3-methoxy-4-methylsulfonylaminophenyl analog (1) was modestly (2.5-fold) more potent than RTX, with an EC(50)=0.106 nM. Further, it resembled RTX in its kinetics and pattern of stimulation of the levels of intracellular calcium in individual cells, as revealed by imaging. Compound 1 displayed modestly enhanced in vitro stability in rat liver microsomes and in plasma, suggesting that it might be a pharmacokinetically more favorable surrogate of resiniferatoxin. Molecular modeling analyses with selected analogues provide evidence that the conformational differences could affect their binding affinities, especially for the ester versus amide at the B-region.
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Bioorganic & Medicinal Chemistry. - 17 : 2 (2009), p. 690-698. -
További szerzők:Choi, Sun Lee, Yoonji Kang, Dong Wook Ryu, HyungChul Maeng, Han-Joo Chung, Suk-Jae Pavlyukovets, Vladimir A. Pearce, Larry V. Tóth Attila (1971-) (biológus) Tran, Richard Wang, Yun Morgan, Matthew A. Blumberg, Peter M. Lee, Jeewoo
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2.

001-es BibID:BIBFORM003725
Első szerző:Chung, Jae-Uk
Cím:Alpha-substituted N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues as potent and stereospecific TRPV1 antagonists / Chung, J. U., Kim, S. Y., Lim, J. O., Choi, H. K., Kang, S. U., Yoon, H. S., Ryu, H., Kang, D. W., Lee, J., Kang, B., Choi, S., Toth, A., Pearce, L. V., Pavlyukovets, V. A., Lundberg, D. J., Blumberg, P. M.
Dátum:2007
Megjegyzések:A series of alpha-substituted N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. alpha-Methyl substituted analogues showed potent and stereospecific antagonism to the action of capsaicin on rat TRPV1 heterologously expressed in Chinese hamster ovary cells. In particular, compounds 14 and 18, which possess the R-configuration, exhibited excellent potencies (respectively, K(i)=41 and 39.2 nM and K(i(ant))=4.5 and 37 nM)
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
antagonists &amp
Calcium
Capsaicin
Cells,Cultured
chemical synthesis
chemistry
Cho Cells
Cricetinae
Cricetulus
inhibitors
metabolism
Models,Molecular
Molecular Structure
pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship
Thiourea
TRPV Cation Channels
Megjelenés:Bioorganic and Medical Chemistry. - 15 : 18 (2007), p. 6043-6053. -
További szerzők:Kim, Su Yeon Lim, Ju-Ok Choi, Hyun-Kyung Kang, Sang-Uk Yoon, Hae-Seok Ryu, HyungChul Kang, Dong Wook Lee, Jeewoo Kang, Bomi Choi, Sun Tóth Attila (1971-) (biológus) Pearce, Larry V. Pavlyukovets, Vladimir A. Lundberg, Daniel J. Blumberg, Peter M.
Internet cím:elektronikus változat
DOI
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3.

001-es BibID:BIBFORM020695
Első szerző:Lim, Ju-Ok
Cím:Conformationally constrained analogues of N'-(4-tert-butylbenzyl)-N-(4-methylsulfonylaminobenzyl)thiourea as TRPV1 antagonists / Lim J. O., Jin M. K., Ryu H., Kang D. W., Lee J., Pearce L. V., Tran R., Toth A., Blumberg P. M.
Dátum:2009
ISSN:0223-5234
Tárgyszavak:Orvostudományok Klinikai orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:European Journal Of Medicinal Chemistry. - 44 : 1 (2009), p. 322-331. -
További szerzők:Jin, Mi-Kyoung Ryu, HyungChul Kang, Dong Wook Lee, Jeewoo Pearce, Larry V. Tran, Richard Tóth Attila (1971-) (biológus) Blumberg, Peter M.
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4.

001-es BibID:BIBFORM005638
Első szerző:Pearce, Larry V.
Cím:Differential modulation of agonist and antagonist structure activity relations for rat TRPV1 by cyclosporin A and other protein phosphatase inhibitors / Pearce, L. V., Toth, A., Ryu, H., Kang, D. W., Choi, H. K., Jin, M. K., Lee, J., Blumberg, P. M.
Dátum:2008
ISSN:0028-1298 (Print)
Megjegyzések:The transient receptor potential V1 channel (vanilloid receptor, TRPV1) represents a promising therapeutic target for inflammatory pain and other conditions involving C-fiber sensory afferent neurons. Sensitivity of TRPV1 is known to be subject to modulation by numerous signaling pathways, in particular by phosphorylation, and we wished to determine whether TRPV1 structure activity relations could be differentially affected. We demonstrate here that the structure activity relations of TRPV1, as determined by (45)Ca(2) uptake, were substantially altered by treatment of the cells with cyclosporin A, an inhibitor of protein phosphatase 2B. Whereas the potency of resiniferatoxin for stimulation of (45)Ca(2) was not altered by cyclosporin A treatment, the potencies of some other agonists were increased up to 8-fold. Among the antagonists examined, potencies were reduced to a lesser extent, ranging from 1- to 2.5-fold. Finally, the efficacy of partial agonists was increased. In contrast to cyclosporin A, okadaic acid, an inhibitor of protein phosphatases 1 and 2A, had little effect on agonist potencies, and calyculin A, an inhibitor of protein phosphatases 1 and 2A but with somewhat different selectivity from that of okadaic acid, caused changes in structure activity relations distinct from those induced by cyclosporin A. Because phosphatase activity differentially modulates the structure activity relations of TRPV1 agonists and antagonists, our findings predict that it may be possible to design agonists and antagonists selective for TRPV1 in a specific regulatory environment. A further implication is that it may be desirable to tailor screening approaches for drug discovery to reflect the desired regulatory state of the targeted TRPV1.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
CHO Cells
Calcium/metabolism
Capsaicin/analogs & derivatives/pharmacology
Cricetinae
Cricetulus
Cyclosporine/ pharmacology
Enzyme Inhibitors/ pharmacology
Phosphoprotein Phosphatases/ antagonists & inhibitors
Rats
Structure-Activity Relationship
TRPV Cation Channels/ agonists/ antagonists & inhibitors
Megjelenés:Naunyn-Schmiedeberg's Archives of Pharmacology. - 377 : 2 (2008), p. 149-157. -
További szerzők:Tóth Attila (1971-) (biológus) Ryu, HyungChul Kang, Dong Wook Choi, Hyun-Kyung Jin, Mi-Kyoung Lee, Jeewoo Blumberg, Peter M.
Internet cím:elektronikus változat
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5.

001-es BibID:BIBFORM005639
Első szerző:Ryu, HyungChul
Cím:Stereospecific high-affinity TRPV1 antagonists : chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues / Ryu, H., Jin, M. K., Kim, S. Y., Choi, H. K., Kang, S. U., Kang, D. W., Lee, J., Pearce, L. V., Pavlyukovets, V. A., Morgan, M. A., Tran, R., Toth, A., Lundberg, D. J., Blumberg, P. M.
Dátum:2008
ISSN:0022-2623 (Print)
Megjegyzések:Previously, we reported the thiourea antagonists 2a and 2b as potent and high affinity TRPV1 antagonists. For further optimization of the lead compounds, a series of their amide and alpha-substituted amide surrogates were investigated and novel chiral N-(2-benzyl-3-pivaloyloxypropyl) 2-[4-(methylsulfonylamino)phenyl]propionamide analogues were characterized as potent and stereospecific rTRPV1 antagonists. In particular, compounds 72 and 73 displayed high binding affinities, with K i values of 4.12 and 1.83 nM and potent antagonism with K i values of 0.58 and 5.2 nM, respectively, in rTRPV1/CHO cells. These values are comparable or more potent than those of 5-iodoRTX under the same assay conditions. A distinctive binding model that includes two hydrophobic pockets is proposed for this series of compounds based on docking studies of 57 and 72 with a homology model of the TM3/4 region of TRPV1.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Animals
Benzeneacetamides
Binding Sites
Binding, Competitive
CHO Cells
Calcium/metabolism
Cricetinae
Cricetulus
Hydrophobicity
Mesylates
Models, Molecular
Radioligand Assay
Rats
Stereoisomerism
Structure-Activity Relationship
TRPV Cation Channels
Megjelenés:Journal of Medicinal Chemistry. - 51 : 1 (2008), p. 57-67. -
További szerzők:Jin, Mi-Kyoung Kim, Su Yeon Choi, Hyun-Kyung Kang, Sang-Uk Kang, Dong Wook Lee, Jeewoo Pearce, Larry V. Pavlyukovets, Vladimir A. Morgan, Matthew A. Tran, Richard Tóth Attila (1971-) (biológus) Lundberg, Daniel J. Blumberg, Peter M.
Internet cím:elektronikus változat
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6.

001-es BibID:BIBFORM058120
Első szerző:Sun, Wei
Cím:2-(4-Methylsulfonylaminophenyl) propanamide TRPV1 antagonists : structure-activity relationships in the B and C-regions / Wei Sun, Keliang Liu, HyungChul Ryu, Dong Wook Kang, Yong Soo Kim, Myeong Seop Kim, Yongsung Cho, Rahul S. Bhondwe, Shivaji A. Thorat, Ho Shin Kim, Larry V. Pearce, Vladimir A. Pavlyukovets, Richard Tran, Matthew A. Morgan, Jozsef Lazar, Christopher B. Ryder, Attila Toth, Peter M. Blumberg, Jeewoo Lee
Dátum:2012
ISSN:0968-0896
Megjegyzések:On the basis of the previous lead N-4-t-butylbenzyl 2-(3-fluoro-4-methylsulfonylaminophenyl) propanamide (3) as a potent TRPV1 antagonist, structure-activity relationships for the B (propanamide part) and C-region (4-t-butylbenzyl part) have been investigated for rTRPV1 in CHO cells. The B-region was modified with dimethyl, cyclopropyl and reverse amides and then the C-region was replaced with 4-substituted phenyl, aryl alkyl and diaryl alkyl derivatives. Among them, compound 50 showed high binding affinity with K(i)=21.5nM, which was twofold more potent than 3 and compound 54 exhibited potent antagonism with K(i(ant))=8.0nM comparable to 3.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Bioorganic & Medicinal Chemistry. - 20 : 3 (2012), p. 1310-1318. -
További szerzők:Liu, Keliang Ryu, HyungChul Kang, Dong Wook Kim, Yong Soo Kim, Myeong Seop Cho, Yongsung Bhondwe, Rahul S. Thorat, Shivaji A. Kim, Ho Shin Pearce, Larry V. Pavlyukovets, Vladimir A. Tran, Richard Morgan, Matthew A. Lázár József Ryder, Christopher B. Tóth Attila (1971-) (biológus) Blumberg, Peter M. Lee, Jeewoo
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