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( Larry V. Pearce ),( Jihyae Ann ),( Peter M. Blumberg ),( Jeewoo Lee ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.5
The capsaicin receptor TRPV1 (transient receptor potential vanilloid 1) has been an object of intense interest for pharmacological development on account of its critical role in nociception. In the course of structure activity analysis, it has become apparent that TRPV1 ligands may vary dramatically in the rates at which they interact with TRPV1, presumably reflecting differences in their abilities to penetrate into the cell. Using a fast penetrating agonist together with an excess of a slower penetrating antagonist, we find that we can induce an agonist response of limited duration and, moreover, the duration of the agonist response remains largely independent of the absolute dose of agonist, as long as the ratio of antagonist to agonist is held constant. This general approach for limiting agonist duration under conditions in which absolute agonist dose is variable should have more general applicability.
Kim, Changhoon,Ann, Jihyae,Lee, Sunho,Kim, Eunhye,Choi, Sun,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.15
<P><B>Abstract</B></P> <P>A series of 2-(3,5-substituted 4-aminophenyl)acetamide and propanamide derivatives were investigated as human TRPV1 antagonists. The analysis of the structure-activity relationship indicated that 2-(3,5-dihalo 4-aminophenyl)acetamide analogues displayed excellent antagonism of <I>h</I>TRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (<B>36</B>) exhibited potent and selective antagonism for <I>h</I>TRPV1 not only to capsaicin but also to NADA and elevated temperature; however, it only displayed weak antagonism to low pH. Further studies indicated that oral administration of antagonist <B>36</B> blocked the hypothermic effect of capsaicin <I>in vivo</I> but demonstrated hyperthermia at that dose. A docking study of <B>36</B> was performed in our established <I>h</I>TRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist <B>1</B>.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Discovery of 2-(3,5-difluoro-4-methylsulfonaminophenyl)propanamides as potent TRPV1 antagonists
Kim, Changhoon,Ann, Jihyae,Lee, Sunho,Sun, Wei,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo Elsevier 2018 Bioorganic & medicinal chemistry letters Vol.28 No.14
<P><B>Abstract</B></P> <P>A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl) propanamide <B>1</B> were investigated as TRPV1 antagonists. The analysis of structure-activity relationship indicated that a fluoro group at the 3- (or/and) 5-position and a methylsulfonamido group at the 4-position were optimal for antagonism of TRPV1 activation by capsaicin. The most potent antagonist <B>6</B> not only exhibited potent antagonism of activation of <I>h</I>TRPV1 by capsaicin, low pH and elevated temperature but also displayed highly potent antagonism of activation of <I>r</I>TRPV1 by capsaicin. Further studies demonstrated that antagonist <B>6</B> blocked the hypothermic effect of capsaicin <I>in vivo</I>, consistent with its <I>in vitro</I> mechanism, and it showed promising analgesic activity in the formalin animal model.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A series of A-region analogues of 2-(3-fluoro-4-methylsufonamidophenyl)propanamide were investigated as TRPV1 antagonists. </LI> <LI> Compound <B>6</B> showed highly potent antagonism toward capsaicin activation. </LI> <LI> Compound <B>6</B> displayed anti-hypothermic effect and promising analgesic activity <I>in vivo</I>. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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>
Characterization of AJH-836, a diacylglycerol-lactone with selectivity for novel PKC isozymes
Cooke, Mariana,Zhou, Xiaoling,Casado-Medrano, Victoria,Lopez-Haber, Cynthia,Baker, Martin J.,Garg, Rachana,Ann, Jihyae,Lee, Jeewoo,Blumberg, Peter M.,Kazanietz, Marcelo G. American Society for Biochemistry and Molecular Bi 2018 The Journal of biological chemistry Vol.293 No.22
<P>Diacylglycerol (DAG) is a key lipid second messenger downstream of cellular receptors that binds to the C1 domain in many regulatory proteins. Protein kinase C (PKC) isoforms constitute the most prominent family of signaling proteins with DAG-responsive C1 domains, but six other families of proteins, including the chimaerins, Ras-guanyl nucleotide-releasing proteins (RasGRPs), and Munc13 isoforms, also play important roles. Their significant involvement in cancer, immunology, and neurobiology has driven intense interest in the C1 domain as a therapeutic target. As with other classes of targets, however, a key issue is the establishment of selectivity. Here, using [H-3]phorbol 12,13-dibutyrate ([H-3]PDBu) competition binding assays, we found that a synthetic DAG-lactone, AJH-836, preferentially binds to the novel PKC isoforms PKC and PKCE relative to classical PKC and PKCII. Assessment of intracellular translocation, a hallmark for PKC activation, revealed that AJH-836 treatment stimulated a striking preferential redistribution of PKCE to the plasma membrane relative to PKC. Moreover, unlike with the prototypical phorbol ester phorbol 12-myristate 13-acetate (PMA), prolonged exposure of cells to AJH-836 selectively down-regulated PKC and PKCE without affecting PKC expression levels. Biologically, AJH-836 induced major changes in cytoskeletal reorganization in lung cancer cells, as determined by the formation of membrane ruffles, via activation of novel PKCs. We conclude that AJH-836 represents a C1 domain ligand with PKC-activating properties distinct from those of natural DAGs and phorbol esters. Our study supports the feasibility of generating selective C1 domain ligands that promote novel biological response patterns.</P>
Pearce, Larry V.,Ann, Jihyae,Jung, Aeran,Thorat, Shivaji A.,Herold, Brienna K. A.,Habtemichael, Amelework D.,Blumberg, Peter M.,Lee, Jeewoo American Chemical Society 2017 Journal of medicinal chemistry Vol.60 No.19
<P>Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl-[<SUP>3</SUP>H])piperidin-1-yl-4-[<SUP>3</SUP>H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2<I>H</I>-benzo[<I>b</I>][1,4]oxazin-8-yl)urea ([<SUP>3</SUP>H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2017/jmcmar.2017.60.issue-19/acs.jmedchem.7b00859/production/images/medium/jm-2017-008593_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm7b00859'>ACS Electronic Supporting Info</A></P>
Lee, Sunho,Kim, Changhoon,Ann, Jihyae,Thorat, Shivaji A.,Kim, Eunhye,Park, Jongmi,Choi, Sun,Blumberg, Peter M.,Frank-Foltyn, Robert,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jee Pergamon Press 2017 Bioorganic & medicinal chemistry letters Vol.27 No.18
<P><B>Abstract</B></P> <P>A series of 1-substituted 3-(<I>t</I>-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for <I>h</I>TRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the <I>S</I>-configuration, providing exceptionally potent antagonists <B>13<I>S</I> </B> and <B>16<I>S</I> </B> with <I>K<SUB>i(CAP)</SUB> </I> =0.1nM. Particularly significant, <B>13<I>S</I> </B> exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for <I>r</I>TRPV1, blocking <I>in vivo</I> the hypothermic action of capsaicin, consistent with their <I>in vitro</I> mechanism. The docking study of compounds <B>13<I>S</I> </B> and <B>16<I>S</I> </B> in our <I>h</I>TRPV1 homology model indicated that the binding modes differed somewhat, with that of <B>13<I>S</I> </B> more closely resembling that of <B>GRT12360</B>.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</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>