In vitro and in vivo pharmacological characterization of the novel neuropeptide S receptor ligands QA1 and PI1 |
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| Institution: | 1. Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy;2. Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy;3. Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA;1. Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Yeungnam University, Daegu, Republic of Korea;2. Regional Center for Respiratory Diseases, Yeungnam University Medical Center, Daegu, Republic of Korea;1. Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun Jilin, China;2. Department of Pharmacology, College of Pharmacy, Jilin University, Changchun, Jilin, China;3. Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, Jilin, China;4. Department of Pharmacology & Therapeutics, University of Manitoba, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada;1. Department of Brain & Cognitive Sciences, DGIST, Daegu 42988, South Korea;2. Department of Biological Sciences, Konkuk University, Seoul 05029, South Korea;1. Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY 11794, USA;2. Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY 11794, USA;3. Department of Biochemistry & Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA;4. Department of Ophthalmology, Stony Brook University, Stony Brook, NY 11794, USA;5. Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8066, USA;6. Department of Ophthalmology and Visual Sciences, Yale University School of Medicine, New Haven, CT 06520-8066, USA;1. Department of Oncology, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;2. Department of Oncology, Akershus University Hospital, Akershus, Norway;3. Institute of Clinical Medicine, University of Oslo, Oslo, Norway;4. Department of Pathology, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;5. Department of Tumour Biology, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;6. Department of Radiology & Nuclear Medicine, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway;7. Department of Gastroenterological Surgery, Oslo University Hospital – Norwegian Radium Hospital, Oslo, Norway |
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| 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 mg kg?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. |
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| Keywords: | Neuropeptide S NPS receptor NPSR antagonists QA1 PI1 Calcium mobilization Mouse Locomotor activity Righting reflex test |
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