Identification of an achiral analogue of J-113397 as potent nociceptin/orphanin FQ receptor antagonist.
To date, J-113397 represents the most potent and selective non peptide NOP receptor antagonist widely used in pharmacological studies. However, the synthesis, purification, and enantiomer separation of this molecule, which contains two chiral centers, is rather difficult and low-yielding. Here, we synthesized and tested a series of simplified J-113397 analogues to investigate the importance of the stereochemistry and the influence of the substituents at position 3 of the piperidine nucleus and on the nitrogen atom of the benzimidazolidinone nucleus. The compound coded as Trap-101, an achiral analogue of J-113397, combines a pharmacological profile similar to that of the parent compound with a practical, high-yielding preparation.
Trapella
Claudio
C
Department of Pharmaceutical Sciences, Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy.
Guerrini
Remo
R
Piccagli
Laura
L
Calo'
Girolamo
G
Carra'
Giacomo
G
Spagnolo
Barbara
B
Rubini
Samantha
S
Fanton
Giulia
G
Hebbes
Christopher
C
McDonald
John
J
Lambert
David G
DG
Regoli
Domenico
D
Salvadori
Severo
S
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009292:Narcotic Antagonists; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor
D001562:Benzimidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; D011994:Recombinant Proteins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000094942:Nociceptin Receptor