Abstract
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 synthesized and tested in binding experiments performed on CHO(hNOP) 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Behavior, Animal / drug effects
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CHO Cells
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Cricetinae
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Cricetulus
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Electric Stimulation
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Guinea Pigs
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Humans
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Ileum / drug effects
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Male
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Mice
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Narcotic Antagonists*
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Nociceptin Receptor
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Piperidines / administration & dosage
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology*
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Protein Binding
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Rats
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Rats, Sprague-Dawley
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Receptors, Opioid / metabolism*
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Spiro Compounds / administration & dosage
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
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Vas Deferens / drug effects
Substances
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1-benzyl-N-(3-(spiroisobenzofuran-1(3H),4'-piperidin-1-yl)propyl)pyrrolidine-2-carboxamide
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Narcotic Antagonists
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Piperidines
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Receptors, Opioid
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Spiro Compounds
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Nociceptin Receptor