title: Discovery of a novel series of orally active nociceptin/orphanin FQ (NOP) receptor antagonists based on a dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran) scaffold.
abstract: Nociceptin/OFQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the ORL1/NOP receptor. Nociceptin appears to regulate a host of physiological functions such as biological reactions to stress, anxiety, mood, and drug abuse, in addition to feeding behaviors. To develop tools to study the function of nociceptin and NOP receptor, our research effort sought to identify orally available NOP antagonists. Our effort led to the discovery of a novel chemical series based on the dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran) scaffold. Herein we show that dihydrospiro(piperidine-4,7'-thieno[2,3-c]pyran)-derived compounds are potent NOP antagonists with high selectivity versus classical opioid receptors (μ, δ, and κ). Moreover, these compounds exhibit sufficient bioavailability to produce a high level of NOP receptor occupancy in the brain following oral administration in rats.
authors.affiliation: Centro de Investigación Lilly, Avenida de la Industria 30, 28108-Alcobendas, Madrid, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Toledo
authors.forename: Concepción
authors.initials: C
authors.lastname: Pedregal
authors.forename: Celia
authors.initials: C
authors.lastname: Lafuente
authors.forename: Nuria
authors.initials: N
authors.lastname: Diaz
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Martinez-Grau
authors.forename: Alma
authors.initials: A
authors.lastname: Jiménez
authors.forename: Ana
authors.initials: A
authors.lastname: Benito
authors.forename: Alicia
authors.initials: A
authors.lastname: Torrado
authors.forename: Carlos
authors.initials: C
authors.lastname: Mateos
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Joshi
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kahl
authors.forename: Karen S
authors.initials: KS
authors.lastname: Rash
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.forename: David B
authors.initials: DB
authors.lastname: Shaw
authors.forename: David
authors.initials: D
authors.lastname: McKinzie
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
mesh_terms: D000284:Administration, Oral; D000818:Animals; D055808:Drug Discovery; D008297:Male; D009292:Narcotic Antagonists; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: D009292:Narcotic Antagonists; D011714:Pyrans; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C000722285:Oprl1 protein, rat