title: In vitro and in vivo pharmacological characterization of the novel neuropeptide S receptor ligands QA1 and PI1.
abstract: The pharmacological activity of the novel neuropeptide S (NPS) receptor (NPSR) ligands QA1 and PI1 was investigated. In vitro QA1 and PI1 were tested in calcium mobilization studies performed in HEK293 cells expressing the recombinant mouse (HEK293mNPSR) and human (HEK293hNPSRIle107 and HEK293hNPSRAsn107) NPSR receptors. In vivo the compounds were studied in mouse righting reflex (RR) and locomotor activity (LA) tests. NPS caused a concentration dependent mobilization of intracellular calcium in the three cell lines with high potency (pEC50 8.73-9.14). In inhibition response curve and Schild protocol experiments the effects of NPS were antagonized by QA1 and PI1. QA1 displayed high potency (pKB 9.60-9.82) behaving as a insurmountable antagonist. However in coinjection experiments QA1 produced a rightward swift of the concentration response curve to NPS without modifying its maximal effects; this suggests that QA1 is actually a slow dissociating competitive antagonist. PI1 displayed a competitive type of antagonism and lower values of potencies (pA2 7.74-8.45). In vivo in mice NPS (0.1 nmol, i.c.v.) elicited arousal promoting action in the RR assay and stimulant effects in the LA test. QA1 (30 mgkg(-1)) was able to partially counteract the arousal promoting NPS effects, while PI1 was inactive in the RR test. In the LA test QA1 and PI1 only poorly blocked the NPS stimulant action. The present data demonstrated that QA1 and PI1 act as potent NPSR antagonists in vitro, however their usefulness for in vivo investigations in mice seems limited probably by pharmacokinetic reasons.
authors.affiliation: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Camarda
authors.forename: C
authors.initials: C
authors.lastname: Ruzza
authors.forename: A
authors.initials: A
authors.lastname: Rizzi
authors.forename: C
authors.initials: C
authors.lastname: Trapella
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: R K
authors.initials: RK
authors.lastname: Reinscheid
authors.forename: G
authors.initials: G
authors.lastname: Calo
mesh_terms: D000577:Amides / Q000008:administration & dosage*; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D008024:Ligands; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics*; D015363:Quinolones / Q000008:administration & dosage*; D018013:Receptors, Neuropeptide / Q000235:genetics* / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects
chemical_list: D000577:Amides; D007093:Imidazoles; D007211:Indoles; D008024:Ligands; C588395:NPSR-PI1 compound; C583306:NPSR-QA1 compound; D009479:Neuropeptides; D015363:Quinolones; D018013:Receptors, Neuropeptide; C583532:neuropeptide S receptor, mouse; C539972:neuropeptide S, mouse; D002118:Calcium
keywords: Calcium mobilization; LA; Locomotor activity; Mouse; NPS; NPS receptor; NPSR; NPSR antagonists; Neuropeptide S; PI1; QA1; RR; Righting reflex test; hNPSR; human NPSR; locomotor activity; mNPSR; mouse NPSR; neuropeptide S; righting reflex