3-Acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid as novel vanilloid receptor agonists

Lee, Jeeyeon; Park, Shin-Ung; Kim, Jiyoung; Kim, Jin-Kwan; Lee, Jiyoun; Oh, Uhtaek; Márquez, Víctor E.; Beheshti, Maryam; Wang, Qiming J.; Modarres, Shayan; Blumberg, Peter M.

doi:10.1016/s0960-894x(99)00513-2

Cited by 17 publications

(9 citation statements)

References 20 publications

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“…To identify the pharmacological preferences of the amino acid residues in the vanilloid pocket, we generated protein-ligand interaction profiles P(I) by docking a library of CAPS analogs to the TRPV1 structures (21,26,27). The profiles are divided according to interaction type (28), electrostatic (E), hydrogen bonding (H), and van der Waals (V) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Exploration of ligand conformational space was performed using OMEGA 2.4.6 (OpenEye) (40,41) with the 94s variant of Merck Molecular Force Field (MMFF94s). FRED, the multiconformational rigid docking algorithm of OpenEye (42)(43)(44), was used for pose prediction of CAPS and RTX and for the docking simulation ofTRPV1 agonist databases (21,26,27). We kept several poses of each ligand for subsequent analysis.…”

Section: Methodsmentioning

confidence: 99%

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Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin

Elokely

Velisetty

Delemotte

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

143

145

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The transient receptor potential cation channel subfamily V member 1 (TRPV1) or vanilloid receptor 1 is a nonselective cation channel that is involved in the detection and transduction of nociceptive stimuli. Inflammation and nerve damage result in the up-regulation of TRPV1 transcription, and, therefore, modulators of TRPV1 channels are potentially useful in the treatment of inflammatory and neuropathic pain. Understanding the binding modes of known ligands would significantly contribute to the success of TRPV1 modulator drug design programs. The recent cryo-electron microscopy structure of TRPV1 only provides a coarse characterization of the location of capsaicin (CAPS) and resiniferatoxin (RTX). Herein, we use the information contained in the experimental electron density maps to accurately determine the binding mode of CAPS and RTX and experimentally validate the computational results by mutagenesis. On the basis of these results, we perform a detailed analysis of TRPV1-ligand interactions, characterizing the protein ligand contacts and the role of individual water molecules. Importantly, our results provide a rational explanation and suggestion of TRPV1 ligand modifications that should improve binding affinity.A dvances in molecular genetics have allowed the identification of a set of ion channels that are expressed in primary afferent neurons and play an important role in the detection and transduction of nociceptive stimuli (1). Among them, transient receptor potential (TRP) channels form a large family. Mammalian TRPs are classified in six subfamilies (2, 3): TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycysteine). TRP channels are nonselective cationic channels, distributed in a diverse range of tissues, with local expression in the free terminals of nociceptive nerve fibers and the skin (4). They are involved in the direct detection of stimuli associated with senses and maintenance of ionic homeostasis (5). The transient receptor potential cation channel subfamily V member 1 (TRPV1) or vanilloid receptor 1 is a polymodal mammalian nociceptive integrator (6) abundantly expressed in the free nerve endings of primary pain sensing afferent Aδ and C fibers (7,8). Structurally, the TRPV1 channel is a homotetramer, symmetrically organized around a solvent exposed central pore (9, 10). Each subunit is formed by six transmembrane helices (S1-S6) with the channel's N and C termini located in the intracellular medium (11).TRPV1 is activated by a wide range of proinflammatory and proalgesic mediators (12), including temperatures above 43°C, external pH, bradykinin, anandamide, arachidonic acid metabolites, jellyfish and spider toxins, and vanilloid. The scope of the TRPV1 pharmacological spectrum (13-15) is mainly in the area of analgesics: novel painkillers could be either TRPV1 agonists or antagonists (16,17). Moving forward toward the rational drug design of TRPV1 modulators requires a basic understanding of how known ligands interact with TRPV1.TRPV1 is...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin

Elokely

Velisetty

Delemotte

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

143

145

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“…These opportunities had not previously been fully revealed through fairly extensive medicinal chemistry (Walpole et al, 1996a,b,c). Using a strategy seeking to incorporate and constrain some of the functional groups contributed by the diterpene moiety of RTX, we have been able to produce novel vanilloid agonists with several hundred-fold enhancement of binding potencies (Lee et al, 1999(Lee et al, , 2001a.…”

Section: Discussionmentioning

confidence: 99%

“…In our ongoing effort to design improved vanilloids, we have identified motifs conferring significantly enhanced potency for rVR1 agonists (Lee et al, 1999(Lee et al, , 2001a(Lee et al, , 2002. Based on these structures, we have designed a series of derivatives that function as rVR1 antagonists (Lee et al, 2001b; J. Lee, Park, et al, manuscript in preparation).…”

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confidence: 99%

High Affinity Antagonists of the Vanilloid Receptor

et al. 2002

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The vanilloid receptor VR1 has attracted great interest as a sensory transducer for capsaicin, protons, and heat, and as a therapeutic target. Here we characterize two novel VR1 antagonists, KJM429 [N-(4-tert-butylbenzyl)-NЈ-[4-(methylsulfonylamino)benzyl]thiourea] and JYL1421 [N-(4-tertbutylbenzyl)-NЈ-[3-fluoro-4-(methylsulfonylamino)benzyl]-thiourea], with enhanced activity compared with capsazepine on rat VR1 expressed in Chinese hamster ovary (CHO) cells. JYL1421, the more potent of the two novel antagonists, inhibited [ 3 H]resiniferatoxin binding to rVR1 with an affinity of 53.5 Ϯ 6.5 nM and antagonized capsaicininduced calcium uptake with an EC 50 of 9.2 Ϯ 1.6 nM, reflecting 25-and 60-fold greater potencies than capsazepine. Both JYL1421 and KJM429 antagonized RTX as well as capsaicin and their mechanism was competitive. The responses to JYL1421 and KJM429 differed for calcium uptake by rVR1 induced by heat or pH. JYL1421 antagonized the response to both pH 6.0 and 5.5, whereas KJM429 antagonized at pH 6.0 but was an agonist at lower pH (Ͻ5.5). For heat, JYL1421 fully antagonized and KJM429 partially antagonized. Capsazepine showed only weak antagonism for both pH and heat. Responses of rVR1 to different activators could thus be differentially affected by different ligands. In cultured dorsal root ganglion neurons, JYL1421 and KJM429 likewise behaved as antagonists for capsaicin, confirming that the antagonism is not limited to heterologous expression systems. Finally, JYL1421 and KJM429 had little or no effect on ATP-induced calcium uptake in CHO cells lacking rVR1, unlike capsazepine. We conclude that JYL1421 is a competitive antagonist of rVR1, blocking response to all three of the agonists (capsaicin, heat, and protons) with enhanced potency relative to capsazepine.A vanilloid receptor (VR1) that is activated by capsaicin, low pH, and temperatures higher than 42°C has been cloned from rat dorsal root ganglia (Caterina et al., 1997;Tominaga et al., 1998). It is a nonselective cation channel, with high permeability for divalent cations, expressed on unmyelinated pain-sensing nerve fibers (C-fibers) and small A␦ fibers in the dorsal root, trigeminal, and nodose ganglia. Initially, activation of VR1 by pungent agonists such as capsaicin leads to excitation of primary sensory neurons gating nociceptive inputs to the central nervous system. Subsequently, these fibers may become desensitized/defunctionalized, and this desensitization forms a basis for the therapeutic use of VR1 agonists . Potential therapeutic applications include detrusor hyperreflexia, postherpetic neuralgia, diabetic neuropathy, cluster headache, osteoarthritis, and pruritus (Rains and Bryson, 1995;Kim and Chancellor, 2000).The exciting potential therapeutic applications for vanilloids have motivated efforts to identify or design novel derivatives with improved properties (Walpole et al., 1993a,b,c;Wrigglesworth et al., 1996). An important advance was the identification of resiniferatoxin (RTX), a diterpene related to the phorbol...

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“…These species differences indicate that in vivo efficacy correlates with capsazepine potency for blocking proton activation of TRPV1. In addition, simplified analogs of resiniferatoxin (Lee et al, 1999), and iodinated analogs of resiniferatoxin (I-RTX; Wahl et al, 2001;Seabrook et al, 2002) and capsaicin (6-iodo-nordihydrocapsaicin; Appendino et al, 2003) have also been reported to be antagonists of TRPV1.…”

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confidence: 99%

AMG 9810 [(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with Antihyperalgesic Properties

Gavva¹,

Tamir²,

Qu³

et al. 2004

J Pharmacol Exp Ther

357

268

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The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810,AMG 9810 is a competitive antagonist of capsaicin activation (IC 50 value for human TRPV1, 24.5 Ϯ 15.7 nM; rat TRPV1, 85.6 Ϯ 39.4 nM) and blocks all known modes of TRPV1 activation, including protons (IC 50 value for rat TRPV1, 294 Ϯ 192 nM; human TRPV1, 92.7 Ϯ 72.8 nM), heat (IC 50 value for rat TRPV1, 21 Ϯ 17 nM; human TRPV1, 15.8 Ϯ 10.8 nM), and endogenous ligands, such as anandamide, N-arachidonyl dopamine, and oleoyldopamine. AMG 9810 blocks capsaicin-evoked depolarization and calcitonin gene-related peptide release in cultures of rat dorsal root ganglion primary neurons. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG 9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. At effective doses, AMG 9810 did not show any significant effects on motor function, as measured by open field locomotor activity and motor coordination tests. AMG 9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.Activation of peripheral nociceptors in humans by capsaicin results in burning pain (Park et al., 1995). Capsaicin, and its ultrapotent analog resiniferatoxin, aided the identification and characterization of the vanilloid receptor 1 (aka VR1 and TRPV1). TRPV1 is a nonselective cation channel with high permeability to calcium (Caterina et al., 1997) and belongs to a superfamily of ion channels known as the transient receptor potential channels or TRPs (Clapham et al., 2001). In addition to activation by exogenous agonists such as capsaicin and resiniferatoxin, TRPV1 can be activated by physical stimuli, such as heat (Ͼ42°C) and protons (pH 5). Based on their structural similarity to capsaicin, several endogenous ligands have been proposed that include anandamide (AEA), 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid,N-arachidonyl dopamine (NADA), N-oleoyldopamine (OLDA), and products of lipoxygenases (Hwang et al., 2000;Olah et al., 2001;Huang et al., 2002;Chu et al., 2003). TRPV1 is up-regulated during inflammation (Ji et al., 2002), and channel activity is modulated by the action of inflammaArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org.doi :

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3-Acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid as novel vanilloid receptor agonists

Cited by 17 publications

References 20 publications

Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin

Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin

High Affinity Antagonists of the Vanilloid Receptor

AMG 9810 [(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)acrylamide], a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with Antihyperalgesic Properties

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