Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core

Autor: Allison Zarkin, Rajwana Jahan, Rajendra Uprety, Yanan Zhang, Charles McElhinny, Rodney Snyder, Elaine Gay, Gabriel Jewula, Heather Bool, Stewart D Clark, Scott Runyon
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Pharmaceuticals, Vol 14, Iss 10, p 1024 (2021)
Druh dokumentu: article
ISSN: 1424-8247
30309425
DOI: 10.3390/ph14101024
Popis: 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 14b reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound 14b 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 14b can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system.
Databáze: Directory of Open Access Journals
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