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. 2021 Oct 6;14(10):1024.
doi: 10.3390/ph14101024.

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

Allison Zarkin  1 , Rajwana Jahan  1 , Rajendra Uprety  1 , Yanan Zhang  1 , Charles McElhinny  1 , Rodney Snyder  1 , Elaine Gay  1 , Gabriel Jewula  2 , Heather Bool  2 , Stewart D Clark  2 , Scott Runyon  1
Affiliations

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

Allison Zarkin et al. Pharmaceuticals (Basel). .

Abstract

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.

Keywords: NPSR; antagonist; anxiolytic; neuropeptide S.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative NPSR antagonists.
Figure 2
Figure 2
Further modifications to SHA led to the identification of novel alkene scaffolds.
Scheme 1
Scheme 1
General synthetic route to alkene-based NPS antagonists.
Scheme 2
Scheme 2
Synthesis of saturated diaryl analogs using the alkene core.
Scheme 3
Scheme 3
Synthesis of 3-N analogs and isobutyl replacement for phenyl in SHA.
Figure 3
Figure 3
Compound 14b displays a right shift on agonist activity of NPS in calcium mobilization assay (Ke).
Scheme 4
Scheme 4
Compound 14b is stable in the presence of excess of glutathione (18 mM).
Figure 4
Figure 4
Pharmacokinetic study of 14b in C57/Bl6 mice. Three animals/timepoint 30 mg/kg i.p. in 1% (NMP), 0.5% Tween 80, 0.5% carboxymethyl cellulose).
Figure 5
Figure 5
Compound 14b attenuates the hyperlocomotory effects of NPS. After 90 min of habituation, mice were pretreated with vehicle or compound 14b (3 mg/kg i.p.), then 10 min later, injected ICV with aCSF or NPS (0.3 nmole). Total distances traveled for the first 10 min after the ICV injection are displayed in the above graph. Compound 14b (3 mg/kg i.p.) significantly decreased the hyperlocomotor effects of NPS. (*** p < 0.001, * p < 0.05; Veh-aCSF n = 6, 14b-aCSF n = 6, Veh-NPS n = 5, 14b-NPS n = 4).
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