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LASSBio-881: an N-acylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally effective against the hypernociception induced by capsaicin or partial sciatic ligation.
Tributino JL
,
Santos ML
,
Mesquita CM
,
Lima CK
,
Silva LL
,
Maia RC
,
Duarte CD
,
Barreiro EJ
,
Fraga CA
,
Castro NG
,
Miranda AL
,
Guimaraes MZ
.
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BACKGROUND AND PURPOSE: Compound LASSBio-881 is an orally effective antinociceptive that binds to cannabinoid receptors and is active mainly on the neurogenic component of pain models. We investigated whether transient receptor potential vanilloid subfamily type 1 (TRPV1) channels are involved in the effects of LASSBio-881.
EXPERIMENTAL APPROACH: Modulation of capsaicin (CAP)- and low pH-induced currents was evaluated in TRPV1-expressing Xenopus oocytes. In vivo effects were evaluated in CAP-induced acute and inflammatory changes in nociception, as well as in partial sciatic ligation-induced thermal hypernociception.
KEY RESULTS: LASSBio-881 inhibited TRPV1 currents elicited by CAP with an IC(50) of 14 microM, and inhibited proton-gated currents by 70% at 20 microM. Functional interaction with CAP was surmountable. Locally applied LASSBio-881 decreased time spent in CAP-elicited nocifensive behaviour by 30%, and given orally it reduced measures of CAP- or carrageenan-evoked thermal hypernociception by 60 and 40% respectively. In addition, LASSBio-881 decreased the paw withdrawal responses to thermal stimuli of animals with sciatic neuropathy 7-11 days after nerve ligation, at a dose of 300 micromol*kg(-1)*day(-1) p.o. At this dose, hyperthermia was not observed within 4 h following oral administration.
CONCLUSIONS AND IMPLICATIONS: LASSBio-881 is a TRPV1 antagonist that apparently competes with CAP. Accordingly, LASSBio- 881 inhibited nociception in models of acute, inflammatory and neuropathic pain presumed to involve TRPV1 signalling. These in vivo actions were not hindered by hyperthermia, a common side effect of other TRPV1 antagonists. We propose that the antinociceptive properties of LASSBio-881 are due to TRPV1 antagonism, although other molecular interactions may contribute to the effects of this multi-target drug candidate.
Ayoub,
Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein.
2004, Pubmed
Ayoub,
Acetaminophen-induced hypothermia in mice is mediated by a prostaglandin endoperoxide synthase 1 gene-derived protein.
2004,
Pubmed
Caterina,
Impaired nociception and pain sensation in mice lacking the capsaicin receptor.
2000,
Pubmed
Caterina,
The capsaicin receptor: a heat-activated ion channel in the pain pathway.
1997,
Pubmed
,
Xenbase
Chuang,
Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.
2001,
Pubmed
,
Xenbase
Cui,
TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists.
2006,
Pubmed
Cuzzocrea,
Potential therapeutic effect of antioxidant therapy in shock and inflammation.
2004,
Pubmed
Davis,
Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia.
2000,
Pubmed
Di Marzo,
Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology.
2007,
Pubmed
Duarte,
Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
2007,
Pubmed
Gonzalez-Serratos,
A novel thienylhydrazone, (2-thienylidene)3,4-methylenedioxybenzoylhydrazine, increases inotropism and decreases fatigue of skeletal muscle.
2001,
Pubmed
Honore,
A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats.
2005,
Pubmed
Jhaveri,
Inhibition of peripheral vanilloid TRPV1 receptors reduces noxious heat-evoked responses of dorsal horn neurons in naïve, carrageenan-inflamed and neuropathic rats.
2005,
Pubmed
Lavich,
A novel hot-plate test sensitive to hyperalgesic stimuli and non-opioid analgesics.
2005,
Pubmed
McNamara,
Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1).
2005,
Pubmed
Mizushima,
Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia.
2005,
Pubmed
NULL,
Guide to Receptors and Channels (GRAC), 4th Edition.
2009,
Pubmed
Prescott,
A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity.
2003,
Pubmed
,
Xenbase
Rawls,
CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.
2002,
Pubmed
Santos,
Ruthenium red and capsazepine antinociceptive effect in formalin and capsaicin models of pain in mice.
1997,
Pubmed
Seltzer,
A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury.
1990,
Pubmed
Szallasi,
Vanilloid (Capsaicin) receptors and mechanisms.
1999,
Pubmed
Szallasi,
The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept.
2007,
Pubmed
Walker,
The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain.
2003,
Pubmed
Wong,
Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.
2009,
Pubmed
Zygmunt,
Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide.
1999,
Pubmed
,
Xenbase
