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Neuropeptide S System: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Rainer K. Reinscheid.

The Neuropeptide S (NPS) system was discovered by a "reverse pharmacology" approach in search for the endogenous ligand of an orphan G protein-coupled receptor. Its peptide ligand and receptor are mainly found in the brain. Effects on anxiety and memory have been described for NPS, as well as genetic associations of the receptor gene with asthma and inflammatory diseases.

  • transmitter
  • GPCR
  • brainstem
  • anxiety
  • memory
  • genetic variation

1. Introduction

Neuropeptide S (NPS) was discovered as a ligand of a previously orphan G protein-coupled receptor (GPCR) by using the “orphan receptor strategy”, also known as “reverse pharmacology” [1]. The receptor (previously known as GPR154 or GPRA) was stably expressed in cells that served as a bait to purify the endogenous ligand from brain extracts [2]. The ligand turned out to be a peptide of 20 amino acids that contains a perfectly conserved serine (single amino acid code “S”) at the N-terminus in all species analyzed, and was thus termed accordingly [3]. NPS is encoded as a single copy peptide by a rather small precursor protein (<90 amino acids) that occurs in the genome of all tetrapods but is absent from fish [4]. The seven N-terminal residues are identical in all tetrapods, as well as the overall 20 amino acid length, while the C-terminal half shows more variation (Figure 1).

Figure 1. Neuropeptide S (NPS) or NPS-like peptide sequences. Residues divergent from the human NPS sequence are highlighted in red. The C-terminal amide (NH2) in the Branchiostoma peptide is encoded by glycine in the precursor protein and therefore identical to the consensus.

A shortened peptide has been identified in a cephalochordate that contains the conserved amino terminal residues [5]. Together with the identification of a distantly-related GPCR from the same class of animals, this suggests a rather complex evolution of the NPS system in bilaterians, where teleost fish may have lost both genes [6].

NPSR1 is also a single-copy gene with moderate similarity to other peptide GPCRs, the closest being vasopressin 1A and oxytocin receptors. NPSR1 is found in the genomes of all tetrapods and no convincing orthologues have been identified in fish genomes [7].

2. General Pharmacology

NPSR1 couples via Gαs and Gαq to elevate intracellular cAMP and Ca2+, thus it is an excitatory GPCR [8]. Activation of mitogen-activated protein kinase (MAPK) pathways and opening of neuronal Ca2+ channels have also been described [8][9][10]. NPS activates its receptor at low nanomolar concentrations and structure-activity relationship (SAR) studies have confirmed the importance of the amino terminus for agonist activity, overlapping with the high evolutionary conservation of this part of the peptide structure [11][12][13]. Focused SAR studies performed on Gly5 lead to the identification of peptidergic NPSR1 antagonists, characterized by a D-amino acid with a short branched aliphatic side chain [14][15]. Some well-characterized NPSR1 antagonists identified in the frame of these studies are [D-Cys(t-Bu)5]NPS, [D-Val5]NPS, and [t-Bu-D-Gly5]NPS [15][16][17].

The prototype synthetic NPSR1 antagonist is SHA 68, belonging to the class of diphenyltetrahydro-1H-oxazolo [3,4-α]pyrazines [18] (Figure 2). SHA 68, and the closely related SHA 66, display nanomolar affinity for NPSR1 in vitro but only limited bioavailability in vivo, due to its high lipophilicity. Using the core structure of SHA 68, several refinements have been made to improve in vivo potency. It appears that slight increases in polarity can indeed cause an increased in vivo potency, albeit with a net loss in receptor affinity [19][20][21][22]. Additional high-throughput drug screening programs have yielded further structures with NPSR1 antagonistic profiles (Figure 2), although with lower in vitro and in vivo potency compared to SHA 68 [23][24][25]. None of these compounds has progressed beyond the preclinical stage yet.

Figure 2. Chemical structures of NPSR1 antagonists. Details about synthesis and pharmacological activities can be found in the original literature. SHA 68 [18], RTI-118 [26], PI1 [27], MLS001018695 [28], NCGC84 [23], QA1 [29], R06039-478 [30].

3. Concluding Remarks

An impressive number of physiological functions have been identified for the NPS system in the relatively short time since its discovery. Together with the plethora of genetic association data for NPSR1 variants with human disease and behaviors, increased efforts to identify therapeutic applications for this interesting transmitter system appear to be promising and warranted. The articles in this Special Issue reflect the continuing progress in our knowledge about the NPS system and its therapeutic potential.

References

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  14. Guerrini, R.; Camarda, V.; Trapella, C.; Calò, G.; Rizzi, A.; Ruzza, C.; Fiorini, S.; Marzola, E.; Reinscheid, R.K.; Regoli, D.; et al. Synthesis and biological activity of human neuropeptide S analogues modified in position 5: Identification of potent and pure neuropeptide S receptor antagonists. J. Med. Chem. 2009, 52, 524–529.
  15. Guerrini, R.; Camarda, V.; Trapella, C.; Caló, G.; Rizzi, A.; Ruzza, C.; Fiorini, S.; Marzola, E.; Reinscheid, R.K.; Regoli, D.; et al. Further studies at neuropeptide S position 5: Discovery of novel neuropeptide S receptor antagonists. J. Med. Chem. 2009, 52, 4068–4071.
  16. Ruzza, C.; Rizzi, A.; Camarda, V.; Pulga, A.; Marzola, G.; Filaferro, M.; Novi, C.; Ruggieri, V.; Marzola, E.; Vitale, G.; et al. [tBu-D-Gly5]NPS, a pure and potent antagonist of the neuropeptide S receptor: In vitro and in vivo studies. Peptides 2012, 34, 404–411.
  17. Camarda, V.; Rizzi, A.; Ruzza, C.; Zucchini, S.; Marzola, G.; Marzola, E.; Guerrini, R.; Salvadori, S.; Reinscheid, R.K.; Regoli, D.; et al. In vitro and in vivo pharmacological characterization of the neuropeptide S receptor antagonist [D-Cys(tBu)5]neuropeptide S. J. Pharmacol. Exp. Ther. 2009, 328, 549–555.
  18. Okamura, N.; Habay, S.A.; Zeng, J.; Chamberlin, A.R.; Reinscheid, R.K. Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor. J. Pharmacol. Exp. Ther. 2008, 325, 893–901.
  19. Ruzza, C.; Rizzi, A.; Trapella, C.; Pela’, M.; Camarda, V.; Ruggieri, V.; Filaferro, M.; Cifani, C.; Reinscheid, R.K.; Vitale, G.; et al. Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68. Peptides 2010, 31, 915–925.
  20. Trapella, C.; Pela, M.; Del Zoppo, L.; Calo, G.; Camarda, V.; Ruzza, C.; Cavazzini, A.; Costa, V.; Bertolasi, V.; Reinscheid, R.K.; et al. Synthesis and separation of the enantiomers of the neuropeptide S receptor antagonist (9 R/S)-3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acid 4-fluoro-benzylamide (SHA 68). J. Med. Chem. 2011, 54, 2738–2744.
  21. Hassler, C.; Zhang, Y.; Gilmour, B.; Graf, T.; Fennell, T.; Snyder, R.; Deschamps, J.R.; Reinscheid, R.K.; Garau, C.; Runyon, S.P. Identification of neuropeptide s antagonists: Structure-Activity relationship studies, x-ray crystallography, and in vivo evaluation. ACS Chem. Neurosci. 2014, 5, 731–744.
  22. Albanese, V.; Ruzza, C.; Marzola, E.; Bernadi, T.; Fabbri, M.; Fantinati, A.; Trapella, C.; Reinscheid, R.K.; Ferrari, F.; Sturaro, C.; et al. Structure-Activity Relationship Studies on Oxazolo[3,4-a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent In Vivo Activity. J. Med. Chem. 2021.
  23. Thorsell, A.; Tapocik, J.D.; Liu, K.; Zook, M.; Bell, L.; Flanigan, M.; Patnaik, S.; Marugan, J.; Damadzic, R.; Dehdashti, S.J.; et al. A novel brain penetrant NPS receptor antagonist, NCGC00185684, blocks alcohol-induced ERK-phosphorylation in the central amygdala and decreases operant alcohol self-administration in rats. J. Neurosci. 2013, 33, 10132–10142.
  24. Batran, R.Z.; Dawood, D.H.; El-Seginy, S.A.; Maher, T.J.; Gugnani, K.S.; Rondon-Ortiz, A.N. Coumarinyl pyranopyrimidines as new neuropeptide S receptor antagonists; design, synthesis, homology and molecular docking. Bioorg. Chem. 2017, 75, 274–290.
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  26. Schmoutz, C.D.; Zhang, Y.; Runyon, S.P.; Goeders, N.E. Antagonism of the neuropeptide S receptor with RTI-118 decreases cocaine self-administration and cocaine-seeking behavior in rats. Pharmacol. Biochem. Behav. 2012, 103, 332–337.
  27. Trotter, B.W.; Nanda, K.K.; Manley, P.J.; Uebele, V.N.; Condra, C.L.; Gotter, A.L.; Menzel, K.; Henault, M.; Stocco, R.; Renger, J.J.; et al. Tricyclic imidazole antagonists of the Neuropeptide S Receptor. Bioorganic Med. Chem. Lett. 2010, 20, 4704–4708.
  28. Patnaik, S.; Marugan, J.J.; Liu, K.; Zheng, W.; Southall, N.; Dehdashti, S.J.; Thorsell, A.; Heilig, M.; Bell, L.; Zook, M.; et al. Structure-activity relationship of imidazopyridinium analogues as antagonists of neuropeptide s receptor. J. Med. Chem. 2013, 56, 9045–9056.
  29. Melamed, J.Y.; Zartman, A.E.; Kett, N.R.; Gotter, A.L.; Uebele, V.N.; Reiss, D.R.; Condra, C.L.; Fandozzi, C.; Lubbers, L.S.; Rowe, B.A.; et al. Synthesis and evaluation of a new series of Neuropeptide S receptor antagonists. Bioorganic Med. Chem. Lett. 2010, 20, 4700–4703.
  30. Runyon, S.; Zhang, Y.; Hassler, C.; Gilmour, B. Composition and method for Neuropeptide S receptor (NPSR) antagonists. World Patent WO/2013/086200, 13 June 2013.
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