Antinociceptive Pharmacology ofN-[[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide, Fumarate (LF22-0542), a Novel Nonpeptidic Bradykinin B1Receptor Antagonist

Porreca, Frank; Vanderah, T. W.; Guo, Wen; Barth, Martine; Dodey, Pierre; Peyrou, V.; Luccarini, Jean‐Michel; Junien, Jean‐Louis; Pruneau, Didier

doi:10.1124/jpet.105.098368

Cited by 39 publications

(19 citation statements)

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“…The mouse carrageenan model has previously been used to characterize novel analgesic compounds [49,50]. Further, galanin levels are endogenously increased following carrageenan insult [51], and intrathecal galanin improves paw withdrawal latency following carageenan administration in rats [52].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2

et al. 2017

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The potential clinical utility of galanin peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia. In addition to possessing potent anticonvulsant efficacy, galanin analogs are analgesic in various assays. The purpose of these studies was to evaluate the lead galanin receptor type 2 (GalR2)-preferring analog, NAX 810-2, in various pain assays, as well as determine any potential for insulin inhibition, growth hormone stimulation, and cognitive impairment. NAX 810-2 was evaluated in mouse (carrageenan, formalin, tail flick, plantar incision) and rat pain models (partial sciatic nerve ligation). NAX 810-2 dose-dependently increased paw withdrawal latency following plantar administration of carrageenan (ED50 4.7 mg/kg). At a dose of 8 mg/kg, NAX 810-2 significantly attenuated nociceptive behaviors following plantar administration of formalin, and this was observed for both phase I (acute) and phase II (inflammatory) components of the formalin behavioral response. NAX-810-2 was active at higher doses in the mouse tail flick model (ED50 20.2 mg/kg) and similarly, reduced mechanical allodynia following plantar incision in mice at a dose of 24 mg/kg. NAX 810-2 also reduced mechanical allodynia in the partial sciatic nerve ligation model at a dose of 4 mg/kg. In addition, NAX 810-2 did not impair insulin secretion at doses of 2.5 and 8 mg/kg (acutely) or at a dose of 8 mg/kg given daily for 5 days. Similarly, 8 mg/kg (twice daily, 5 days) of NAX 810-2 did not increase growth hormone levels. These results demonstrate that NAX 810-2 possesses a favorable pre-clinical profile as a novel and first-in-class analgesic.

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Section: Discussionmentioning

confidence: 99%

Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2

et al. 2017

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“…LF22-0542 showed high affinity for human and mouse B 1 R with virtually no affinity for the human B 2 R; a selectivity index of at least 4000 times was obtained when LF22-0542 was profiled throughout binding or cell biology assays on 64 other G-protein-coupled receptor, 10 ion channels, and seven enzymes [25]. LF22-0542 blocked pain behavior in various inflammatory and neuropathic pain models in rats and mice and was found inactive in B 1 R knockout mice models of inflammatory pain [25], [26], [27]. Fresh solution was prepared daily by dissolving the compound in saline 0.9% and sterilizing the solution by filtration (0.20 µm mesh).…”

Section: Methodsmentioning

confidence: 99%

Ocular Application of the Kinin B1 Receptor Antagonist LF22-0542 Inhibits Retinal Inflammation and Oxidative Stress in Streptozotocin-Diabetic Rats

et al. 2012

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PurposeKinin B1 receptor (B1R) is upregulated in retina of Streptozotocin (STZ)-diabetic rats and contributes to vasodilation of retinal microvessels and breakdown of the blood-retinal barrier. Systemic treatment with B1R antagonists reversed the increased retinal plasma extravasation in STZ rats. The present study aims at determining whether ocular application of a water soluble B1R antagonist could reverse diabetes-induced retinal inflammation and oxidative stress.MethodsWistar rats were made diabetic with STZ (65 mg/kg, i.p.) and 7 days later, they received one eye drop application of LF22-0542 (1% in saline) twice a day for a 7 day-period. The impact was determined on retinal vascular permeability (Evans blue exudation), leukostasis (leukocyte infiltration using Fluorescein-isothiocyanate (FITC)-coupled Concanavalin A lectin), retinal mRNA levels (by qRT-PCR) of inflammatory (B1R, iNOS, COX-2, ICAM-1, VEGF-A, VEGF receptor type 2, IL-1β and HIF-1α) and anti-inflammatory (B2R, eNOS) markers and retinal level of superoxide anion (dihydroethidium staining).ResultsRetinal plasma extravasation, leukostasis and mRNA levels of B1R, iNOS, COX-2, VEGF receptor type 2, IL-1β and HIF-1α were significantly increased in diabetic retinae compared to control rats. All these abnormalities were reversed to control values in diabetic rats treated with LF22-0542. B1R antagonist also significantly inhibited the increased production of superoxide anion in diabetic retinae.ConclusionB1R displays a pathological role in the early stage of diabetes by increasing oxidative stress and pro-inflammatory mediators involved in retinal vascular alterations. Hence, topical application of kinin B1R antagonist appears a highly promising novel approach for the treatment of diabetic retinopathy.

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“…We speculated that 5-HT would be released during phase 1 as a response to puncture by the formalin injection needle. In peripheral inflammation, not only 5-HT, but also histamine, prostaglandin E2, substance P, noradrenaline (Hong and Abbott, 1994), and bradykinin (Porreca et al, 2006) are released in the peripheral tissue. One possible reason for this unexpected finding is the affinity of the 5-HT antagonists for other receptors that may contribute to nociceptive behavior.…”

Section: -Ht Release In the Formalin Testmentioning

confidence: 99%

“…For example, ketanserin also inhibits a1-adrenoceptors (Hoyer et al, 2002). In peripheral inflammation, not only 5-HT, but also histamine, prostaglandin E2, substance P, noradrenaline (Hong and Abbott, 1994), and bradykinin (Porreca et al, 2006) are released in the peripheral tissue. Non-specific binding may produce antinociceptive effects in phase 1 of the formalin test.…”

Section: -Ht Release In the Formalin Testmentioning

confidence: 99%

The nociceptive mechanism of 5‐hydroxytryptamine released into the peripheral tissue in acute inflammatory pain in rats

Nakajima

Obata

Ito

et al. 2009

European Journal of Pain

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The present study examined the contribution of 5-hydroxytryptamine (5-HT) to acute peripheral inflammatory pain in rats. We used formalin test in this study. After formalin injection into the rat hind paw, biphasic pain-related behavior (phases 1 and 2) was observed. A microdialysis study revealed that 5-HT was released into the formalin injection site in a formalin concentration-dependent manner (1.25-5%), and its peak time was 18min after the injection. Previous studies suggest that peripheral 5-HT2 receptors are involved in inflammatory pain. Therefore, we next examined whether 5-HT2A and 5-HT2C receptors are involved, and from where 5-HT is released in the formalin test. Local pretreatment with a selective 5-HT2A receptor antagonist, ketanserin, and selective 5-HT2C receptor antagonists, RS102221 and SB242084, inhibited the number of flinches in early part of phase 2 (phase 2A) of the formalin test in a dose-dependent manner. Peripheral pretreatment with sodium cromoglycate (cromolyn), a mast cell membrane stabilizer, completely suppressed 5-HT release and inhibited phase 2 responses of the formalin test. These drugs inhibited c-fos expression in the superficial layer of the spinal dorsal horn of segments L4-5 at 2h after formalin injection. These results indicate that 5-HT released into peripheral tissue and its receptors, 5-HT2A as well as 5-HT2C, at the periphery have an important role in pain-related behaviors during acute peripheral inflammation.

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Antinociceptive Pharmacology ofN-[[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide, Fumarate (LF22-0542), a Novel Nonpeptidic Bradykinin B₁Receptor Antagonist

Cited by 39 publications

References 39 publications

Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2

Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2

Ocular Application of the Kinin B1 Receptor Antagonist LF22-0542 Inhibits Retinal Inflammation and Oxidative Stress in Streptozotocin-Diabetic Rats

The nociceptive mechanism of 5‐hydroxytryptamine released into the peripheral tissue in acute inflammatory pain in rats

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