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Kinetics of penetration influence the apparent potency of vanilloids on TRPV1.
Lazar, Jozsef,Braun, Derek C,Tó,th, Attila,Wang, Yun,Pearce, Larry V,Pavlyukovets, Vladimir A,Blumberg, Peter M,Garfield, Susan H,Wincovitch, Stephen,Choi, Hyun-Kyung,Lee, Jeewoo American Society for Pharmacology and Experimental 2006 Molecular pharmacology Vol.69 No.4
<P>Evidence that the ligand binding site of TRPV1 lies on the inner face of the plasma membrane and that much of the TRPV1 itself is localized to internal membranes suggests that the rate of ligand entry into the cell may be an important determinant of the kinetics of ligand action. In this study, we synthesized a BODIPY TR-labeled fluorescent capsaicin analog (CHK-884) so that we could directly measure ligand entry. We report that CHK-884 penetrated only slowly into Chinese hamster ovary (CHO) cells expressing rat TRPV1, with a t1/2 of 30 +/- 4 min, and localized in the endoplasmic reticulum and Golgi. Although CHK-884 was only weakly potent for TRPV1 binding (Ki = 6400 +/- 230 nM), it was appreciably more potent when assayed by intracellular calcium imaging and was 3.2-fold more potent with a 1-h incubation time (37 nM) than with a 5-min incubation time. Olvanil, a highly lipophilic vanilloid, yielded an EC50 of 4.3 nM upon intracellular calcium imaging with an incubation time of 1 h, compared with an EC50 value of 29.5 nM for calcium imaging assayed at 5 min. Likewise, the antagonist 5-iodo-resiniferatoxin (5-iodo-RTX) displayed a Ki of 4.2 pM if incubated with CHO-TRPV1 cells for 2 h before addition of capsaicin compared with 1.5 nM if added simultaneously. We conclude that some vanilloids may have slow kinetics of uptake; this slow uptake may affect assessment of structure activity relations and may represent a significant factor for vanilloid drug design.</P>
The SAR analysis of TRPV1 agonists with the α-methylated B-region
Cho, Yongsung,Kim, Myeong Seop,Kim, Ho Shin,Ann, Jihyae,Lee, Jiyoun,Pearce, Larry V.,Pavlyukovets, Vladimir A.,Morgan, Matthew A.,Blumberg, Peter M.,Lee, Jeewoo Elsevier 2012 Bioorganic & medicinal chemistry letters Vol.22 No.16
<P>A series of TRPV1 agonists with amide, reverse amide, and thiourea groups in the B-region and their corresponding α-methylated analogues were investigated. Whereas the α-methylation of the amide B-region enhanced the binding affinities and potencies as agonists, that of the reverse amide and thiourea led to a reduction in receptor affinity. The analysis indicated that proper hydrogen bonding as well as steric effects in the B-region are critical for receptor binding.</P>
Lee, Jin Hee,Lee, Yoonji,Ryu, HyungChul,Kang, Dong Wook,Lee, Jeewoo,Lazar, Jozsef,Pearce, Larry V,Pavlyukovets, Vladimir A,Blumberg, Peter M,Choi, Sun ESCOM ; Kluwer Academic Publishers 2011 Journal of computer-aided molecular design Vol.25 No.4
<P>The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.</P>
Chung, Jae-Uk,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,Toth, Attila,Pearce, Larry V.,Pavlyukovets, Vladimir 이화여자대학교 약학연구소 2008 藥學硏究論文集 Vol.- No.18
A series of α-substituted N-(4-tert-butylbenzyl)-N-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPVl receptor antagonists. α-Methyl substituted analogues showed potent and stereospecific antagonism to the action of capsaicin on rat TRPVl 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).