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Research ArticleNEUROPHARMACOLOGY

In Vitro and in Vivo Pharmacological Characterization of the Neuropeptide S Receptor Antagonist [d-Cys(tBu)5]Neuropeptide S

Valeria Camarda, Anna Rizzi, Chiara Ruzza, Silvia Zucchini, Giuliano Marzola, Erika Marzola, Remo Guerrini, Severo Salvadori, Rainer K. Reinscheid, Domenico Regoli and Girolamo Calò
Journal of Pharmacology and Experimental Therapeutics February 2009, 328 (2) 549-555; DOI: https://doi.org/10.1124/jpet.108.143867
Valeria Camarda
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Anna Rizzi
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Chiara Ruzza
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Silvia Zucchini
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Giuliano Marzola
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Erika Marzola
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Remo Guerrini
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Severo Salvadori
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Rainer K. Reinscheid
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Domenico Regoli
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Girolamo Calò
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Abstract

Neuropeptide S (NPS) was identified as the endogenous ligand of an orphan receptor now referred to as the NPS receptor (NPSR). In the frame of a structure-activity study performed on NPS Gly5, the NPSR ligand [d-Cys(tBu)5]NPS was identified. [d-Cys(tBu)5]NPS up to 100 μM did not stimulate calcium mobilization in human embryonic kidney (HEK) 293 cells stably expressing the mouse NPSR; however, in a concentration-dependent manner, the peptide inhibited the stimulatory effects elicited by 10 and 100 nM NPS (pKB, 6.62). In Schild analysis experiments [d-Cys(tBu)5]NPS (0.1–100 μM) produced a concentration-dependent and parallel rightward shift of the concentration-response curve to NPS, showing a pA2 value of 6.44. Ten micromolar [d-Cys(tBu)5]NPS did not affect signaling at seven NPSR unrelated G-protein-coupled receptors. In the mouse righting reflex (RR) recovery test, NPS given at 0.1 nmol i.c.v. reduced the percentage of animals losing the RR in response to 15 mg/kg diazepam and their sleeping time. [d-Cys(tBu)5]NPS (1–10 nmol) was inactive per se but dose-dependently antagonized the arousal-promoting action of NPS. Finally, NPSR-deficient mice were similarly sensitive to the hypnotic effects of diazepam as their wild-type littermates. However, the arousal-promoting action of 1 nmol NPS could be detected in wild-type but not in mutant mice. In conclusion, [d-Cys(tBu)5]NPS behaves both in vitro and in vivo as a pure and selective NPSR antagonist but with moderate potency. Moreover, using this tool together with receptor knockout mice studies, we demonstrated that the arousal-promoting action of NPS is because of the selective activation of the NPSR protein.

Footnotes

  • This work was supported by the University of Ferrara [FAR Grant]; the Italian Ministry of University [Grant PRIN 2006]; and the National Institutes of Health National Institute of Mental Health [Grant MH71313].

  • V.C. and A.R. contributed equally to this work.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.143867.

  • ABBREVIATIONS: NPS, neuropeptide S; NPSR, NPS receptor; SHA 66, 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide; SHA 68, 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide; HEK, human embryonic kidney; HEK293mNPSR, HEK293 cells expressing the mouse NPSR; RR, righting reflex recovery; NPSR(-/-), NPSR knockout mice; PCR, polymerase chain reaction; CHO, Chinese hamster ovary.

    • Received July 23, 2008.
    • Accepted October 28, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 3
1 Mar 2021
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Research ArticleNEUROPHARMACOLOGY

In Vitro and in Vivo Pharmacological Characterization of the Neuropeptide S Receptor Antagonist [d-Cys(tBu)5]Neuropeptide S

Valeria Camarda, Anna Rizzi, Chiara Ruzza, Silvia Zucchini, Giuliano Marzola, Erika Marzola, Remo Guerrini, Severo Salvadori, Rainer K. Reinscheid, Domenico Regoli and Girolamo Calò
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 549-555; DOI: https://doi.org/10.1124/jpet.108.143867

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Research ArticleNEUROPHARMACOLOGY

In Vitro and in Vivo Pharmacological Characterization of the Neuropeptide S Receptor Antagonist [d-Cys(tBu)5]Neuropeptide S

Valeria Camarda, Anna Rizzi, Chiara Ruzza, Silvia Zucchini, Giuliano Marzola, Erika Marzola, Remo Guerrini, Severo Salvadori, Rainer K. Reinscheid, Domenico Regoli and Girolamo Calò
Journal of Pharmacology and Experimental Therapeutics February 1, 2009, 328 (2) 549-555; DOI: https://doi.org/10.1124/jpet.108.143867
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