Abstract
Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca2+ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPS-induced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.
Footnotes
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This study was supported in part by the National Institute of Mental Health (Grant MH-71313; to R.K.R.) and by the National Institute of Neurological Disorders and Stroke (Grant NS-27600; to A.R.C.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.135103.
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ABBREVIATIONS: NPS, neuropeptide S; NPSR, neuropeptide S 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; ESI, electrospray ionization; THF, tetrahydrofuran; DMSO, dimethyl sulfoxide; BSA, bovine serum albumin; GPCR, G protein-coupled receptor; PBS, phosphate-buffered saline; PK, pharmacokinetic; BBB, blood-brain barrier; LC/MS/MS, liquid chromatography-coupled tandem mass spectrometry; ANOVA, analysis of variance; HEK, human embryonic kidney; Veh, vehicle; Fmoc, 9H-fluoren-9-ylmethoxy carbonyl.
- Received December 7, 2007.
- Accepted March 11, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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