Identification and Biological Characterization of 6-Aryl-7-isopropylquinazolinones as Novel TRPV1 Antagonists that Are Effective in Models of Chronic Pain

Culshaw, Andrew J.; Bevan, Stuart; Christiansen, M. Skytte; Copp, Prafula; Davis, Andrew Jackson; Davis, Clare; Dyson, Alex; Dziadulewicz, Edward K.; Edwards, Lee J.; Eggelte, Hendrikus; Fox, Alyson; Gentry, Clive; Groarke, Alex; Hallett, Allan; Hart, Terance W.; Hughes, Glyn A; Knights, S.; Kotsonis, Peter; Lee, Wai; Lyothier, Isabelle; McBryde, Andrew; McIntyre, Peter; Paloumbis, George; Panesar, Moh; Patel, Sadhana; Seiler, Max-Peter; Yaqoob, Mohammed; Zimmermann, Kaspar

doi:10.1021/jm051058x

Cited by 59 publications

(33 citation statements)

References 15 publications

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“…The difference could therefore be linked to the sciatic nerve lesion that is different in the two models. In the present study, eugenol signifi cantly reduced hyperalgesia which is consistent with prior studies (Guénette et al, 2007;Park et al, 2009) as well as mechanical allodynia, consistent with other studies showing that a TRPV1 antagonist reduced mechanical allodynia (Cui et al, 2006;Culshaw et al, 2006;Beaudry et al, 2010). These results show that eugenol may have an effect on mechanical sensitivity as well.…”

Section: Alleviation Of Painsupporting

confidence: 93%

“…Heat opens the channel pore of the VR1, whereas low pH would lower the receptor's heat threshold (Tominaga et al, 1998). Mechanical transduction has also been demonstrated for this receptor (Cui et al, 2006;Culshaw et al, 2006;Honore et al, 2005;Pomonis et al, 2003). TRPV1 agonists and antagonists have demonstrated an analgesic effect on both infl ammatory and neuropathic pain (Caterina et al, 1997;Ohkubo and Shibabta, 1997;Tominaga et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Intrathecal eugenol administration alleviates neuropathic pain in male Sprague‐Dawley rats

Lionnet

Beaudry

Vachon

2010

Phytotherapy Research

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The main objective of this study was to determine the central effect of eugenol on neuropathic pain when injected intrathecally at the level of the lumbar spinal cord. In a preliminary study the penetrability of eugenol was evaluated in the CNS of rats. Blood, brain and spinal cord samples were collected at selected time points following eugenol administration and concentrations were determined by tandem liquid chromatography-mass spectrometry. Brain-to-plasma and spinal cord-to-plasma ratios (3.3 and 6.7, respectively) suggest that eugenol penetrates relatively well the CNS of rats, with a preferential distribution in the spinal cord. Following the induction of neuropathic pain in rats using the sciatic nerve ligation model, intrathecal injections of eugenol were done to evaluate the central effect of eugenol. Treatment with 50 μg of eugenol significantly decreased secondary mechanical allodynia after 15 min, 2 h and 4 h (p < 0.05; <0.005; <0.05, respectively) and improved thermal hyperalgesia after 2 h and 4 h (p < 0.001 and p < 0.05). The results support the hypothesis that eugenol may alleviate neuropathic pain, both allodynia and hyperalgesia, by acting centrally most probably at the level of the dorsal horn of the spinal cord where vanilloid receptors can be found.

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Section: Alleviation Of Painsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Intrathecal eugenol administration alleviates neuropathic pain in male Sprague‐Dawley rats

Lionnet

Beaudry

Vachon

2010

Phytotherapy Research

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“…BCTP was identified from a medicinal chemistry lead optimization program after a high-throughput screen (Culshaw et al, 2006; Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

7-tert-Butyl-6-(4-Chloro-Phenyl)-2-Thioxo-2,3-Dihydro-1H-Pyrido[2,3-d]Pyrimidin-4-One, a Classic Polymodal Inhibitor of Transient Receptor Potential Vanilloid Type 1 with a Reduced Liability for Hyperthermia, Is Analgesic and Ameliorates Visceral Hypersensitivity

Nash¹,

McIntyre²,

Groarke³

et al. 2012

J Pharmacol Exp Ther

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The therapeutic potential of transient receptor potential vanilloid type 1 (TRPV1) antagonists for chronic pain has been recognized for more than a decade. However, preclinical and clinical data revealed that acute pharmacological blockade of TRPV1 perturbs thermoregulation, resulting in hyperthermia, which is a major hurdle for the clinical development of these drugs. Here, we describe the properties of 7-tert-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (BCTP), a TRPV1 antagonist with excellent analgesic properties that does not induce significant hyperthermia in rodents at doses providing maximal analgesia. BCTP is a classic polymodal inhibitor of TRPV1, blocking activation of the human channel by capsaicin and low pH with IC 50 values of 65.4 and 26.4 nM, respectively. Similar activity was observed with rat TRPV1, and the inhibition by BCTP was competitive and reversible. BCTP also blocked heat-induced activation of TRPV1. In rats, the inhibition of capsaicin-induced mechanical hyperalgesia was observed with a D 50 value of 2 mg/kg p.o. BCTP also reversed visceral hypersensitivity and somatic inflammatory pain, and using a model of neuropathic pain in TRPV1 null mice we confirmed that its analgesic properties were solely through the inhibition of TRPV1. We were surprised to find that BCTP administered orally induced only a maximal 0.6°C increase in core body temperature at the highest tested doses (30 and 100 mg/kg), contrasting markedly with N- [4-({6-[4-(trifluoromethyl) phenyl]pyrimidin-4-yl}oxy)-1,3-benzothiazol-2-yl]acetamide (AMG517), a clinically tested TRPV1 antagonist, which induced marked hyperthermia (Ͼ1°C) at doses eliciting submaximal reversal of capsaicin-induced hyperalgesia. The combined data indicate that TRPV1 antagonists with a classic polymodal inhibition profile can be identified where the analgesic action is separated from the effects on body temperature.

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“…One established sequence selective for binding cholesterol is the putative CRAC motif, first identified in the benzodiazepine receptor (43) and later identified in many other proteins and peptides (40,44,45). This motif is defined as a sequence pattern of -(Leu/Val-(X) 1-5 -Tyr-(X) 1-5 -Arg/Lys)-, in which (X) [1][2][3][4][5] represents between one and five residues of any amino acid (40,45). Cholesterol interacts with the CRAC motif with both attractive van der Waals interactions between hydrophobic surfaces and electrostatic interactions between the positively charged Arg or Lys residue and the cholesterol -OH group (40,45).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Binding Motif in the S5 Helix That Confers Cholesterol Sensitivity to the TRPV1 Ion Channel

Picazo-Juárez

Romero-Suárez

Nieto-Posadas

et al. 2011

Journal of Biological Chemistry

131

113

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The TRPV1 ion channel serves as an integrator of noxious stimuli with its activation linked to pain and neurogenic inflammation. Cholesterol, a major component of cell membranes, modifies the function of several types of ion channels. Here, using measurements of capsaicin-activated currents in excised patches from TRPV1-expressing HEK cells, we show that enrichment with cholesterol, but not its diastereoisomer epicholesterol, markedly decreased wild-type rat TRPV1 currents. Substitutions in the S5 helix, rTRPV1-R579D, and rTRPV1-F582Q, decreased this cholesterol response and rTRPV1-L585I was insensitive to cholesterol addition. Two human TRPV1 variants, with different amino acids at position 585, had different responses to cholesterol with hTRPV1-Ile 585 being insensitive to this molecule. However, hTRPV1-I585L was inhibited by cholesterol addition similar to rTRPV1 with the same S5 sequence. In the absence of capsaicin, cholesterol enrichment also inhibited TRPV1 currents induced by elevated temperature and voltage. These data suggest that there is a cholesterol-binding site in TRPV1 and that the functions of TRPV1 depend on the genetic variant and membrane cholesterol content. The transient receptor potential (TRP)3 family of ion channels is found throughout the animal kingdom and has been shown to subserve numerous functions. One extensively studied member of this family is the TRPV1 (Vanilloid 1) channel. Structurally, TRPV1 is thought to be a tetramer comprised of subunits each with six transmembrane domains (S1-S6), with the putative pore of the channel located between S5 and S6. It also contains large intracellular amino and carboxyl termini that have been shown to be involved both in channel gating and regulation (for review, see Ref.

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Identification and Biological Characterization of 6-Aryl-7-isopropylquinazolinones as Novel TRPV1 Antagonists that Are Effective in Models of Chronic Pain

Cited by 59 publications

References 15 publications

Intrathecal eugenol administration alleviates neuropathic pain in male Sprague‐Dawley rats

Intrathecal eugenol administration alleviates neuropathic pain in male Sprague‐Dawley rats

7-tert-Butyl-6-(4-Chloro-Phenyl)-2-Thioxo-2,3-Dihydro-1H-Pyrido[2,3-d]Pyrimidin-4-One, a Classic Polymodal Inhibitor of Transient Receptor Potential Vanilloid Type 1 with a Reduced Liability for Hyperthermia, Is Analgesic and Ameliorates Visceral Hypersensitivity

Identification of a Binding Motif in the S5 Helix That Confers Cholesterol Sensitivity to the TRPV1 Ion Channel

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