The pharmacological activity of the novel neuropeptide S (NPS) receptor (NPSR) ligands QA1 and PI1 wasinvestigated. In vitro QA1 and PI1 were tested in calcium mobilization studies performed in HEK293 cellsexpressing the recombinant mouse (HEK293mNPSR) and human (HEK293hNPSRIle107and 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 celllines with high potency (pEC508.73–9.14). In inhibition response curve and Schild protocol experimentsthe effects of NPS were antagonized by QA1 and PI1. QA1 displayed high potency (pKB9.60–9.82) behavingas a insurmountable antagonist. However in coinjection experiments QA1 produced a rightward swift ofthe concentration response curve to NPS without modifying its maximal effects; this suggests that QA1 isactually a slow dissociating competitive antagonist. PI1 displayed a competitive type of antagonism andlower values of potencies (pA27.74–8.45). In vivo in mice NPS (0.1 nmol, i.c.v.) elicited arousal promotingaction in the RR assay and stimulant effects in the LA test. QA1 (30 mg kg−1) was able to partially counteractthe arousal promoting NPS effects, while PI1 was inactive in the RR test. In the LA test QA1 and PI1 onlypoorly blocked the NPS stimulant action. The present data demonstrated that QA1 and PI1 act as potentNPSR antagonists in vitro, however their usefulness for in vivo investigations in mice seems limitedprobably by pharmacokinetic reasons.
In vitro and in vivo pharmacological characterization of the novel neuropeptide S receptor ligands QA1 and PI1
CAMARDA, Valeria;RUZZA, Chiara;RIZZI, Anna;TRAPELLA, Claudio;GUERRINI, Remo;CALO', Girolamo
2013
Abstract
The pharmacological activity of the novel neuropeptide S (NPS) receptor (NPSR) ligands QA1 and PI1 wasinvestigated. In vitro QA1 and PI1 were tested in calcium mobilization studies performed in HEK293 cellsexpressing the recombinant mouse (HEK293mNPSR) and human (HEK293hNPSRIle107and 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 celllines with high potency (pEC508.73–9.14). In inhibition response curve and Schild protocol experimentsthe effects of NPS were antagonized by QA1 and PI1. QA1 displayed high potency (pKB9.60–9.82) behavingas a insurmountable antagonist. However in coinjection experiments QA1 produced a rightward swift ofthe concentration response curve to NPS without modifying its maximal effects; this suggests that QA1 isactually a slow dissociating competitive antagonist. PI1 displayed a competitive type of antagonism andlower values of potencies (pA27.74–8.45). In vivo in mice NPS (0.1 nmol, i.c.v.) elicited arousal promotingaction in the RR assay and stimulant effects in the LA test. QA1 (30 mg kg−1) was able to partially counteractthe arousal promoting NPS effects, while PI1 was inactive in the RR test. In the LA test QA1 and PI1 onlypoorly blocked the NPS stimulant action. The present data demonstrated that QA1 and PI1 act as potentNPSR antagonists in vitro, however their usefulness for in vivo investigations in mice seems limitedprobably by pharmacokinetic reasons.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
