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.
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.
Trapella
Claudio
C
Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy.
Fischetti
Carmela
C
Pela'
Michela
M
Lazzari
Ilaria
I
Guerrini
Remo
R
Calo'
Girolamo
G
Rizzi
Anna
A
Camarda
Valeria
V
Lambert
David G
DG
McDonald
John
J
Regoli
Domenico
D
Salvadori
Severo
S
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004558:Electric Stimulation; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects; D000094942:Nociceptin Receptor
C543193:1-benzyl-N-(3-(spiroisobenzofuran-1(3H),4'-piperidin-1-yl)propyl)pyrrolidine-2-carboxamide; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor