N-(3-Acyloxy-2-Benzylpropyl)-N′-Dihydroxytetrahydrobenzazepine and Tetrahydroisoquinoline Thiourea Analogues as Vanilloid Receptor Ligands

Lee, Jeeyeon; Lee, Jiyoun; Szabó, Tamás; Gonzalez, Adamar F; Welter, Jacqueline D.; Blumberg, Peter M.

doi:10.1016/s0968-0896(01)00068-2

Cited by 21 publications

(20 citation statements)

References 20 publications

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“…Consistent with the finding that VR1 channel opening in response to different agonists, namely capsaicin, heat, and pH, can be associated with different dependence on antagonist structure is our previous observation that minor changes in structure can shift the activity of a ligand from agonist to antagonist (Lee et al, 2001b). For example, the replacement of benzoate with 3,4-dimethylbenzoate in the antagonist 2-benzyl-3-{[(6,7-dihydroxy-3,4-dihydro-2(1H)-isoquinolinyl) carbothioyl]amino}propyl benzoate converts the compound into an agonist (Lee et al, 2001b).…”

Section: Discussionsupporting

confidence: 86%

“…Building on our previous efforts to design high-affinity vanilloid agonists, we have also been able to develop an extensive series of antagonists for rVR1 (Lee et al, 2001b At the practical level, a contribution of this study is that we have identified a rVR1 antagonist, JYL1421, which is 25-to 60-fold more potent than capsazepine, the antagonist currently in common use. It thus falls in a similar potency range to 5-iodo-RTX.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the replacement of benzoate with 3,4-dimethylbenzoate in the antagonist 2-benzyl-3-{[(6,7-dihydroxy-3,4-dihydro-2(1H)-isoquinolinyl) carbothioyl]amino}propyl benzoate converts the compound into an agonist (Lee et al, 2001b). Similarly, 2-iodo-RTX was described as an agonist for human VR1 with 75% of the …”

Section: Discussionmentioning

confidence: 99%

“…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). In the present study, we have characterized in detail, using CHO cells heterologously expressing rVR1, two of these antagonists, KJM429 and JYL1421.…”

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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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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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High Affinity Antagonists of the Vanilloid Receptor

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“…In particular, we have described 20-to 50-fold differences in potencies of vanilloids as assayed by inhibition of [ 3 H]resiniferatoxin binding and by induction of 45 Ca 2ϩ uptake (Acs et al, 1996;Lee et al, 2001). Although these results suggested distinct receptors mediating these responses, cloned, heterologously expressed TRPV1 was able to account both for [ 3 H]resiniferatoxin binding as well as for 45 Ca 2ϩ uptake .…”

Section: Ibtu Antagonized the Elevation In Intracellular Camentioning

confidence: 99%

Design of a High-Affinity Competitive Antagonist of the Vanilloid Receptor Selective for the Calcium Entry-Linked Receptor Population

Tóth¹,

Blumberg²,

Chen³

et al. 2004

Mol Pharmacol

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We describe the synthesis and characterization of N-(4-chlorobenzyl) -NЈ-(4-hydroxy-3-iodo-5-methoxybenzyl)thiourea (IBTU), a novel antagonist of the vanilloid receptor 1 (TRPV1 or VR1). IBTU competitively inhibited 45 Ca 2ϩ uptake into CHO cells heterologously expressing rat TRPV1, whether induced by capsaicin or resiniferatoxin (K i ϭ 99 Ϯ 23 and 93 Ϯ 34 nM, respectively). IBTU was thus somewhat more potent (5-fold) than capsazepine. In contrast to its antagonism of vanilloid-induced calcium uptake, IBTU (30 M) inhibited [ 3 H]resiniferatoxin binding to TRPV1 by less than 10%. We hypothesize that these dramatically distinct potencies reflect different fractions of TRPV1 in this system: namely, a minor plasma membrane fraction controlling 45 Ca 2ϩ uptake, and the predominant intracellular fraction that dominates the [ 3 H]resiniferatoxin binding measurements. Intracellular Ca 2ϩ imaging supports this explanation.IBTU antagonized the elevation in intracellular Ca 2ϩ in response to 50 nM capsaicin with an IC 50 of 106 Ϯ 35 nM. Likewise, 600 nM IBTU was able to antagonize the elevation in intracellular Ca 2ϩ in response to 100 pM resiniferatoxin in the presence of normal (1.8 mM) extracellular Ca 2ϩ , where the increase in intracellular calcium reflects calcium influx. In contrast, in the absence of extracellular Ca 2ϩ , where in this system resiniferatoxin induces a modest increase in calcium from intracellular stores, IBTU was unable to block the response to resiniferatoxin, although the TRPV1 antagonist 5-iodoresiniferatoxin was able to do so. In summary, IBTU is a novel, potent TRPV1 antagonist with marked selectivity between subpopulations of TRPV1 and may permit the function of these distinct pools to be explored and potentially exploited.The vanilloid receptor TRPV1 is a polymodal integrator of noxious stimuli (Caterina et al., 1997), including low pH, heat, and ligands such as capsaicin, the pungent constituent in red pepper. Because of its function as a nociceptor, TRPV1 has attracted much attention as a novel, potential therapeutic target for the treatment of pain and other conditions involving C fiber sensory neurons (Kress and Zeilhofer, 1999;Caterina and Julius, 2001). Such applications include bladder hyperreflexia, detrusor instability, postmastectomy pain, mucositis, interstitial cystitis, pharyngitis, pancreatitis, enteritis, cellulitis, postherpetic neuralgia, peripheral neuropathy, arthritis, and bony fractures (Robbins, 2000).The characterization of novel natural products, such as resiniferatoxin, an ultrapotent TRPV1 agonist, and the emerging wealth of synthetic capsaicin analogs are driving a rapidly developing appreciation of the complexities of vanilloid pharmacology. Two general strategies for therapeutic intervention have received much attention. First, activation of TRPV1 by agonists is followed by desensitization/defunctionalization. As illustrated for resiniferatoxin or for olvanil, the acute response of pungency and the chronic response of desensitization/defunctionalization...

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Synthesis of Substituted 2,3‐Dihydro‐1H‐2‐benzazepines and 1,2‐Dihydroisoquinolines Using an Isomerization‐Ring‐Closing Metathesis Strategy: Scope and Limitations

et al. 2007

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An isomerization‐ring‐closing metathesis (RCM) approach was used for the synthesis of substituted 2,3‐dihydro‐1H‐2‐benzazepines and 1,2‐dihydroisoquinolines. The 2,3‐dihydro‐1H‐2‐benzazepines were obtained from N‐protected N‐{2‐[(1E)‐prop‐1‐en‐1‐yl]benzyl}prop‐2‐en‐1‐amines by RCM reaction. A double isomerisation reaction on the N‐protected N‐(2‐allylbenzyl)prop‐2‐en‐1‐amines and a subsequent RCM afforded the substituted 1,2‐dihydroisoquinolines. Finally, a selective isomerization of the allylamine group of N‐protected N‐(2‐allylbenzyl)prop‐2‐en‐1‐amines by [RuClH(CO)(PPh3)3], followed by RCM, did not afford the expected 2,5‐dihydro‐1H‐2‐benzazepines but afforded products resulting from deallylation and isomerization of the starting material.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

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N-(3-Acyloxy-2-Benzylpropyl)-N′-Dihydroxytetrahydrobenzazepine and Tetrahydroisoquinoline Thiourea Analogues as Vanilloid Receptor Ligands

Cited by 21 publications

References 20 publications

High Affinity Antagonists of the Vanilloid Receptor

High Affinity Antagonists of the Vanilloid Receptor

Design of a High-Affinity Competitive Antagonist of the Vanilloid Receptor Selective for the Calcium Entry-Linked Receptor Population

Synthesis of Substituted 2,3‐Dihydro‐1H‐2‐benzazepines and 1,2‐Dihydroisoquinolines Using an Isomerization‐Ring‐Closing Metathesis Strategy: Scope and Limitations

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