Structure-activity studies on the nociceptin/orphanin FQ receptor antagonist 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4′-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide

被引：24
|
作者：
Trapella, Claudio [1 ,2 ]
Fischetti, Carmela [3 ,4 ,5 ]
Pela', Michela [1 ,2 ]
Lazzari, Ilaria [1 ,2 ]
Guerrini, Remo [1 ,2 ]
Calo', Girolamo [3 ,4 ]
Rizzi, Anna [3 ,4 ]
Camarda, Valeria [3 ,4 ]
Lambert, David G. [5 ]
McDonald, John [5 ]
Regoli, Domenico [3 ,4 ]
Salvadori, Severo [1 ,2 ]
机构：
[1] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy
[2] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy
[3] Univ Ferrara, Pharmacol Sect, Dept Expt & Clin Med, I-44100 Ferrara, Italy
[4] Univ Ferrara, Natl Inst Neurosci, I-44100 Ferrara, Italy
[5] Univ Leicester, Leicester Royal Infirm,Pharmacol & Therapeut Grp, Dept Cardiovasc Sci, Div Anaesthesia Crit Care & Pain Management, Leicester LE1 5WW, Leics, England
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 14期
关键词：
SAR studies; NOP receptor antagonists; Receptor and [S-35]GTP gamma S binding; Mouse vas deferens; Calcium mobilization; Tail withdrawal assay; PHARMACOLOGICAL CHARACTERIZATION; IN-VITRO; AGONIST; POTENT; UFP-101; PROFILE; ORL1;
D O I：
10.1016/j.bmc.2009.05.068
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Twelve derivatives of the nociceptin/orphanin FQ (N/OFQ) receptor (NOP) antagonist 1-benzyl-N-{3-[spiroisobenzofuran-1(3H),4'-piperidin-1-yl]propyl} pyrrolidine-2-carboxamide (Comp 24) were synthesised and tested in binding experiments performed on CHOhNOP cell membranes. Among them, a novel interesting NOP receptor antagonist (compound 35) was identified by blending chemical moieties taken from different NOP receptor ligands. In vitro in various assays, Compound 35 consistently behaved as a pure, highly potent (pA(2) in the range 8.0-9.9), competitive and NOP selective antagonist. However compound 35 was found inactive when challenged against N/OFQ in vivo in the mouse tail withdrawal assay. Thus the usefulness of the novel NOP ligand compound 35 is limited to in vitro investigations. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码：5080 / 5095
页数：16
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