In vitro and in vivo pharmacological characterization of the novel NK1 receptor selective antagonist Netupitant

Rizzi, Anna; Campi, Barbara; Camarda, Valeria; Molinari, Stefano; Cantoreggi, Sergio; Regoli, Doménico; Pietra, Claudio; Calò, Girolamo

doi:10.1016/j.peptides.2012.06.010

Cited by 58 publications

(51 citation statements)

References 30 publications

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“…These findings are fully consistent with results obtained using bioassay techniques and animal tissues (Regoli et al, 1988;1994) and cells expressing recombinant human receptors (Rizzi et al, 2012). PWT2 tachykinin derivatives mimicked the stimulatory effects of the natural peptides with similar maximal effects in the three cell lines.…”

Section: Bjp C Ruzza Et Alsupporting

confidence: 89%

“…We cannot explain those differences, but the present results indicate that agonist potency may or may not be affected by the application of PWT technology depending on the peptide sequence and the receptor interacting with the ligand. Independently of agonist potency, the interaction of PWT derivatives with NK receptors seems to mirror that of the natural sequences as the NK receptor antagonists (aprepitant, GR159897, SB222200) displayed inhibitor potencies against PWT2-SP, PWT2-NKA and PWT2-NKB, close to those obtained in earlier studies against SP, NKA and NKB (Rizzi et al, 2012). In addition, aprepitant behaved as an insurmountable antagonist against both PWT2-SP and SP with similar potency.…”

Section: Figuresupporting

confidence: 73%

“…Previous studies (Hylden and Wilcox, 1981) recently replicated in our laboratories (Rizzi et al, 2012) demonstrated that the i.t. injection of SP in mice elicits a typical nociceptive behaviour consisting of scratching (S), biting (B) and licking (L).…”

Section: Nociceptive Behaviours Induced By It Pwt2-sp In Micementioning

confidence: 73%

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Pharmacological characterization of tachykinin tetrabranched derivatives

Ruzza

Rizzi

Malfacini

et al. 2014

British J Pharmacology

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Keywordstachykinins; substance P; PWT2-SP; NK1 receptor; calcium mobilization; bioluminescence resonance energy transfer; guinea pig ileum; rat urinary bladder; nociceptive behaviour induced by spinal substance P; mice BACKGROUND AND PURPOSEPeptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity and reproducibility. Using this technique, we have synthesized and pharmacologically characterized the tetrabranched derivatives of the tachykinins, substance P (SP), neurokinin A (NKA) and B (NKB). EXPERIMENTAL APPROACHThe following in vitro assays were used: calcium mobilization in cells expressing human recombinant NK receptors, BRET studies of G-protein -NK1 receptor interaction, guinea pig ileum and rat urinary bladder bioassays. Nociceptive behavioural response experiments were performed in mice following intrathecal injection of PWT2-SP. KEY RESULTSIn calcium mobilization studies, PWT tachykinin derivatives behaved as full agonists at NK receptors with a selectivity profile similar to that of the natural peptides. NK receptor antagonists display similar potency values when tested against PWT2 derivatives and natural peptides. In BRET and bioassay experiments PWT2-SP mimicked the effects of SP with similar potency, maximal effects and sensitivity to aprepitant. After intrathecal administration in mice, PWT2-SP mimicked the nociceptive effects of SP, but with higher potency and a longer-lasting action. Aprepitant counteracted the effects of PWT2-SP in vivo. CONCLUSIONS AND IMPLICATIONSThe present study has shown that the PWT technology can be successfully applied to the peptide sequence of tachykinins to generate tetrabranched derivatives characterized with a pharmacological profile similar to the native peptides. In vivo, PWT2-SP displayed higher potency and a marked prolongation of action, compared with SP.

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Section: Bjp C Ruzza Et Alsupporting

confidence: 89%

Section: Figuresupporting

confidence: 73%

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Pharmacological characterization of tachykinin tetrabranched derivatives

Ruzza

Rizzi

Malfacini

et al. 2014

British J Pharmacology

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“…For netupitant, the affinity for NK 1 receptors was found with a pK b of 8.87 in Chinese hamster ovary cells, whereas in vivo the compound inhibited SP-induced scratching, biting, and licking with a median effective dose of 0.5 mg/kg p.o. (Ness and Gebhart, 1988;Rizzi et al, 2012). In this investigation, netupitant produced a trend toward inhibition of paw withdrawal, although the postinjection values were not significantly different from baseline values.…”

Section: Discussioncontrasting

confidence: 48%

Synergistic Effect of 5-Hydroxytryptamine 3 and Neurokinin 1 Receptor Antagonism in Rodent Models of Somatic and Visceral Pain

Meerveld

Mohammadi

Tyler

et al. 2014

J Pharmacol Exp Ther

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Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT 3 ) and tachykinergic neurokinin 1 (NK 1 ) receptor-mediated responses. This study investigated the efficacy of a 5-HT 3 antagonist, palonosetron, and a NK 1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P , 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK 1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome.

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“…17,18 Netupitant is present in the frontal and occipital cortex, the striatum, the anterior cingulate, and the lateral and medial temporal cortex. 18 Palonosetron is a 5-HT 3 receptor antagonist that inhibits the serotonin secreted from stimulation by chemotherapy.…”

mentioning

confidence: 99%

Netupitant/Palonosetron

2015

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In vitro and in vivo pharmacological characterization of the novel NK1 receptor selective antagonist Netupitant

Cited by 58 publications

References 30 publications

Pharmacological characterization of tachykinin tetrabranched derivatives

Pharmacological characterization of tachykinin tetrabranched derivatives

Synergistic Effect of 5-Hydroxytryptamine 3 and Neurokinin 1 Receptor Antagonism in Rodent Models of Somatic and Visceral Pain

Netupitant/Palonosetron

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