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

Duarte, Carolina D.; Tributino, Jorge Luiz Mendonça; Lacerda, Daniel I.; Martins, Marina V.; Alexandre-Moreira, Magna Suzana; Dutra, Fernando; Bechara, Etelvino J.H.; De-Paula, Francine S.; Goulart, Marília Oliveira Fonseca; Ferreira, Juliano; Calixto, João B.; Nunes, Marise P.; Bertho, Álvaro Luiz; Miranda, Ana Luísa P.; Barreiro, Eliezer J.; Fraga, Carlos A.M.

doi:10.1016/j.bmc.2007.01.013

Cited by 58 publications

(34 citation statements)

References 52 publications

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“…Here, we report that LASSBio-881, previously described as an antinociceptive compound (Duarte et al, 2007), is a TRPV1 antagonist. The TRPV1 channel has been pointed out as a promising target for new analgesic drugs, because changes in its function and expression underlie painful conditions.…”

Section: Discussionmentioning

confidence: 80%

“…Oral administration of LASSBio-881, 300 mmol·kg -1 , did not produce a significant change in temperature at all times measured ( Figure 4). As high concentrations of LASSBio-881 are able to inhibit COX (Duarte et al, 2007), this could explain the lack of hyperthermia; hence, a lower dose was also applied to test this hypothesis. Indeed, 100 mmol·kg -1 LASSBio-881 caused mild hyperthermia relative to vehicle, which was statistically significant at 60 and 90 min following its administration.…”

Section: Highest Dose Of Lassbio-881 Does Not Cause Hyperthermiamentioning

confidence: 99%

“…LASSBio-881 is one of a series of 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone compounds derived from safrole (Duarte et al, 2007), structurally related to LASSBio-294 (Gonzalez-Serratos et al, 2001) and to nimesulide. This series was developed with the aim of obtaining a compound with improved analgesic and anti-inflammatory activity relative to LASSBio-294.…”

Section: Introductionmentioning

confidence: 99%

“…The presence of a 3,5-di-tertbutyl-4-hydroxyphenyl moiety conferred considerable antioxidant activity to LASSBio-881 and was expected to enhance its efficacy in attenuating deleterious manifestations of both acute and chronic inflammatory responses (Cuzzocrea et al, 2004). However, unlike LASSBio-294 and nimesulide, LASSBio-881 was found to inhibit nociception only in the early neurogenic phase of the formalin test and in the hot plate, with limited anti-inflammatory effects in rodents (Duarte et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The bioisosteric relationships between N-acylhydrazones like LASSBio-881 and unsaturated fatty acids like the endocannabinoid anandamide prompted binding studies that revealed LASSBio-881 as a ligand of type 1 cannabinoid receptors (CB 1) (Duarte et al, 2007). It was then postulated that antioxidant and CB1-dependent mechanisms contributed to the antinociceptive effect of this novel compound.…”

Section: Introductionmentioning

confidence: 99%

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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

Santos

Mesquita

et al. 2010

British J Pharmacology

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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 IC50 of 14 mM, and inhibited proton-gated currents by 70% at 20 mM. 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 mmol·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.

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Section: Discussionmentioning

confidence: 80%

Section: Highest Dose Of Lassbio-881 Does Not Cause Hyperthermiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Santos

Mesquita

et al. 2010

British J Pharmacology

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Tin‐Mediated One‐Pot Preparation of β‐Trifluoromethyl‐β‐ acylhydrazonyl Carbonyl Compounds

et al. 2019

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A concise and efficient protocol for the preparation of β‐trifluoromethyl‐β‐acylhydrazonyl carbonyl compounds was developed from multicomponent one‐pot reactions of trifluoroacetaldehyde methyl hemiacetal, acylhydrazines and 2‐bromocarbonyl compounds in the presence of tin powder. The reactions can be carried out under mild reaction conditions to give the products in good to excellent yields.

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Design and Synthesis of 2‐Phenoxynicotinic Acid Hydrazides as Anti‐inflammatory and Analgesic Agents

Moradi

Navidpour

Amini

et al. 2010

Archiv der Pharmazie

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A series of 2-phenoxynicotinic acid hydrazides were synthesized and evaluated for their analgesic and anti-inflammatory activities. Several compounds having an unsubstituted phenyl/4-pyridyl or C-4 methoxy substituent on the terminal phenyl ring showed moderate to high analgesic or anti-inflammatory activity in comparison to mefenamic acid as the reference drug. The compounds with highest anti-inflammatory activity were subjected to in vitro COX-1/COX-2 inhibition assays and showed moderate to good COX-1 and weak COX-2 inhibition activities.

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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

Cited by 58 publications

References 52 publications

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

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

Tin‐Mediated One‐Pot Preparation of β‐Trifluoromethyl‐β‐ acylhydrazonyl Carbonyl Compounds

Design and Synthesis of 2‐Phenoxynicotinic Acid Hydrazides as Anti‐inflammatory and Analgesic Agents

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