Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core
Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a no...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/10/1024 |
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| author | Allison Zarkin Rajwana Jahan Rajendra Uprety Yanan Zhang Charles McElhinny Rodney Snyder Elaine Gay Gabriel Jewula Heather Bool Stewart D Clark Scott Runyon |
| author_facet | Allison Zarkin Rajwana Jahan Rajendra Uprety Yanan Zhang Charles McElhinny Rodney Snyder Elaine Gay Gabriel Jewula Heather Bool Stewart D Clark Scott Runyon |
| author_sort | Allison Zarkin |
| collection | DOAJ |
| description | Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a novel core scaffold (+) N-benzyl-3-(2-methylpropyl)-1-oxo-3-phenyl-1H,3H,4H,5H,6H,7H-furo[3,4-c]pyridine-5-carboxamide with potent NPSR antagonist activity in vitro. Pharmacokinetic parameters demonstrate that <b>14b</b> reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound <b>14b</b> was able to block NPS (0.3 nmol)-stimulated locomotor activity in C57/Bl6 mice at 3 mg/kg (i.p.), indicating potent in vivo activity for the structural class. This suggests that <b>14b</b> can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system. |
| first_indexed | 2024-03-10T06:17:17Z |
| format | Article |
| id | doaj.art-774898e303094257a56345421ce84511 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T06:17:17Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-774898e303094257a56345421ce845112023-11-22T19:36:16ZengMDPI AGPharmaceuticals1424-82472021-10-011410102410.3390/ph14101024Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 CoreAllison Zarkin0Rajwana Jahan1Rajendra Uprety2Yanan Zhang3Charles McElhinny4Rodney Snyder5Elaine Gay6Gabriel Jewula7Heather Bool8Stewart D Clark9Scott Runyon10Research Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USADepartment of Pharmacology and Toxicology, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USADepartment of Pharmacology and Toxicology, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USADepartment of Pharmacology and Toxicology, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USAResearch Triangle Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USAActivation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a novel core scaffold (+) N-benzyl-3-(2-methylpropyl)-1-oxo-3-phenyl-1H,3H,4H,5H,6H,7H-furo[3,4-c]pyridine-5-carboxamide with potent NPSR antagonist activity in vitro. Pharmacokinetic parameters demonstrate that <b>14b</b> reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound <b>14b</b> was able to block NPS (0.3 nmol)-stimulated locomotor activity in C57/Bl6 mice at 3 mg/kg (i.p.), indicating potent in vivo activity for the structural class. This suggests that <b>14b</b> can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system.https://www.mdpi.com/1424-8247/14/10/1024neuropeptide SantagonistanxiolyticNPSR |
| spellingShingle | Allison Zarkin Rajwana Jahan Rajendra Uprety Yanan Zhang Charles McElhinny Rodney Snyder Elaine Gay Gabriel Jewula Heather Bool Stewart D Clark Scott Runyon Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core Pharmaceuticals neuropeptide S antagonist anxiolytic NPSR |
| title | Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core |
| title_full | Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core |
| title_fullStr | Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core |
| title_full_unstemmed | Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core |
| title_short | Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core |
| title_sort | identification of a novel neuropeptide s receptor antagonist scaffold based on the sha 68 core |
| topic | neuropeptide S antagonist anxiolytic NPSR |
| url | https://www.mdpi.com/1424-8247/14/10/1024 |
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