Neuropeptide S (NPS) regulates different biological functions by selectively activating a G protein coupled receptor named NPSR. Previous studies identified [D-Pen5]NPS as a NPSR antagonist. This study investigated the structure activity relationship of [D-Pen5]NPS by alkylation of the thiol group of D-Pen with different aliphatic and aromatic moieties. Nine compounds were synthesised and assayed in calcium mobilization studies, performed in HEK293 cells expressing the recombinant mouse NPSR. All compounds behaved as pure NPSR antagonists of moderate to high potency, in a similar manner to the reference peptide. The most potent compounds were obtained using alkylating groups as cyclic aromatic moieties. [D-Pen(p-tBuBzl)5]NPS, the best compound of this series, was further investigated in vivo, where it fully prevented the stimulatory effects of supraspinal NPS on mouse locomotor activity. [D-Pen(p-tBuBzl)5]NPS is proposed as a novel pharmacological tool which could be useful to investigate in vitro and in vivo biological functions regulated by the NPS/NPSR receptor system.

[D-Pen(p-tBuBzl)5]NPS, a novel ligand for the neuropeptide S receptor: structure activity and pharmacological studies

RUZZA, Chiara;MALFACINI, Davide;PELA', Michela;TRAPELLA, Claudio;SALVADORI, Severo;CALO', Girolamo;GUERRINI, Remo
2014

Abstract

Neuropeptide S (NPS) regulates different biological functions by selectively activating a G protein coupled receptor named NPSR. Previous studies identified [D-Pen5]NPS as a NPSR antagonist. This study investigated the structure activity relationship of [D-Pen5]NPS by alkylation of the thiol group of D-Pen with different aliphatic and aromatic moieties. Nine compounds were synthesised and assayed in calcium mobilization studies, performed in HEK293 cells expressing the recombinant mouse NPSR. All compounds behaved as pure NPSR antagonists of moderate to high potency, in a similar manner to the reference peptide. The most potent compounds were obtained using alkylating groups as cyclic aromatic moieties. [D-Pen(p-tBuBzl)5]NPS, the best compound of this series, was further investigated in vivo, where it fully prevented the stimulatory effects of supraspinal NPS on mouse locomotor activity. [D-Pen(p-tBuBzl)5]NPS is proposed as a novel pharmacological tool which could be useful to investigate in vitro and in vivo biological functions regulated by the NPS/NPSR receptor system.
Ruzza, Chiara; L., del Zoppo; Malfacini, Davide; Pela', Michela; Trapella, Claudio; P., Grieco; Salvadori, Severo; Calo', Girolamo; Guerrini, Remo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1984212
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