Synthesis and in vitro evaluation of a novel iodinated resiniferatoxin derivative that is an agonist at the human vanilloid VR1 receptor

McDonnell, Mark E.; Zhang, Sui Po; Dubin, Adrienne E.; Dax, Scott L.

doi:10.1016/s0960-894x(02)00127-0

Cited by 39 publications

(34 citation statements)

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“…at ASPET Journals on May 10, 2018 molpharm.aspetjournals.org efficacy of capsaicin, whereas 5-iodo-RTX was an antagonist (McDonnell et al, 2002). In the present study, the difference in behavior of JYL1421 compared with KJM429 reflects merely the m-fluoro substitution on the phenyl ring of the A-region.…”

Section: Antagonists Of Vanilloid Receptor 955mentioning

confidence: 48%

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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: Antagonists Of Vanilloid Receptor 955mentioning

confidence: 48%

“…In vivo, intrathecal administration of 5-iodo-RTX to mice blocked the acute pain response to injection of capsaicin. For human VR1, 5-iodo-RTX was reported to antagonize with an ID 50 of 27 nM (McDonnell et al, 2002).…”

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High Affinity Antagonists of the Vanilloid Receptor

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“…Symanowicz et al (2004) have recently reported that intranasal I-RTX produces what they call dramatic changes in basal breathing pattern. The fact that both noniodinated RTX and RTX iodinated in position 2 (instead of 5) are agonists of the TRPV-1 (McDonnell et al, 2002) makes it plausible to think about an intrinsic TRPV-1 agonistic activity of I-RTX. However, several experiments aimed at finding a TRPV-1 agonistic activity of I-RTX in vitro have failed (Wahl et al, 2001).…”

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Lipopolysaccharide fever is initiatedviaa capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor

Dogan

Patel

Rudaya

et al. 2004

British Journal of Pharmacology

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1 As pretreatment with intraperitoneal capsaicin CAP), an agonist of the vanilloid receptor known as VR1 or transient receptor potential channel-vanilloid receptor subtype 1 (TRPV-1), has been shown to block the first phase of lipopolysaccharide (LPS) fever in rats, this phase is thought to depend on the TRPV-1-bearing sensory nerve fibers originating in the abdominal cavity. However, our recent studies suggest that CAP blocks the first phase via a non-neural mechanism. In the present work, we studied whether this mechanism involves the TRPV-1. 2 Adult Long-Evans rats implanted with chronic jugular catheters were used. 3 Pretreatment with CAP (5 mg kg À1 , i.p.) 10 days before administration of LPS (10 mg kg À1 , i.v.) resulted in the loss of the entire first phase and a part of the second phase of LPS fever. 4 Pretreatment with the ultrapotent TRPV-1 agonist resiniferatoxin (RTX; 2, 20, or 200 mg kg À1 , i.p.) 10 days before administration of LPS had no effect on the first and second phases of LPS fever, but it exaggerated the third phase at the highest dose. The latter effect was presumably due to the known ability of high doses of TRPV-1 agonists to cause a loss of warm sensitivity, thus leading to uncontrolled, hyperpyretic responses. , i.p.) did not affect LPS fever, but blocked the immediate hypothermic response to acute administration of CAP. 6 It is concluded that LPS fever is initiated via a non-neural mechanism, which is CAP-sensitive but RTX-and CPZ-insensitive. The action of CAP on this mechanism is likely TRPV-1-independent. It is speculated that this mechanism may be the production of prostaglandin E 2 by macrophages in LPSprocessing organs.

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“…The discovery that the introduction of an iodine atom on the vanillyl moiety of RTX agonist modulates its pharmacological activity depending on the position of the halogen ended up with the identification of 5-iodoRTX (15, Fig. 4) as a potent antagonist of TRPV1 (IC 50 = 3.9 nM) [73,112]. This compound produced analgesic activity in vivo and it is currently in clinical studies.…”

Section: Trpv1 Competitive Antagonistsmentioning

confidence: 99%

Physiology and Pharmacology of the Vanilloid Receptor

Messeguer

Planells-Cases²,

Ferrer‐Montiel

2006

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Abstract:The identification and cloning of the vanilloid receptor 1 (TRPV1) represented a significant step for the understanding of the molecular mechanisms underlying the transduction of noxious chemical and thermal stimuli by peripheral nociceptors. TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 channel activity is remarkably potentiated by pro-inflammatory agents, a phenomenon that is thought to underlie the peripheral sensitisation of nociceptors that leads to thermal hyperalgesia. Cumulative evidence is building a strong case for the involvement of this receptor in the etiology of both peripheral and visceral inflammatory pain, such as inflammatory bowel disease, bladder inflammation and cancer pain. The validation of TRPV1 receptor as a key therapeutic target for pain management has thrust intensive drug discovery programs aimed at developing orally active antagonists of the receptor protein. Nonetheless, the real challenge of these drug discovery platforms is to develop antagonists that preserve the physiological activity of TRPV1 receptors while correcting over-active channels. This is a condition to ensure normal pro-prioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury. Recent and exciting advances in the function, dysfunction and modulation of this receptor will be the focus of this review.

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Synthesis and in vitro evaluation of a novel iodinated resiniferatoxin derivative that is an agonist at the human vanilloid VR1 receptor

Cited by 39 publications

References 6 publications

High Affinity Antagonists of the Vanilloid Receptor

High Affinity Antagonists of the Vanilloid Receptor

Lipopolysaccharide fever is initiatedviaa capsaicin-sensitive mechanism independent of the subtype-1 vanilloid receptor

Physiology and Pharmacology of the Vanilloid Receptor

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