title: Evaluation of the analgesic effect of 4-anilidopiperidine scaffold containing ureas and carbamates.
abstract: Fentanyl is a powerful opiate analgesic typically used for the treatment of severe and chronic pain, but its prescription is strongly limited by the well-documented side-effects. Different approaches have been applied to develop strong analgesic drugs with reduced pharmacologic side-effects. One of the most promising is the design of multitarget drugs. In this paper we report the synthesis, characterization and biological evaluation of twelve new 4-anilidopiperidine (fentanyl analogues). In vivo hot-Plate test, shows a moderate antinociceptive activity for compounds OMDM585 and OMDM586, despite the weak binding affinity on both μ and δ-opioid receptors. A strong inverse agonist activity in the GTP-binding assay was revealed suggesting the involvement of alternative systems in the brain. Fatty acid amide hydrolase inhibition was evaluated, together with binding assays of cannabinoid receptors. We can conclude that compounds OMDM585 and 586 are capable to elicit antinociception due to their multitarget activity on different systems involved in pain modulation.
authors.affiliation: a Dipartimento di Chimica e Tecnologia del Farmaco , Sapienza Università di Roma , Rome , Italy .
authors.forename: Ludovica
authors.initials: L
authors.lastname: Monti
authors.affiliation: b Dipartimento di Chimica , Sapienza Università di Roma , Rome , Italy .
authors.forename: Azzurra
authors.initials: A
authors.lastname: Stefanucci
authors.affiliation: c Istituto Superiore di Sanità, Dipartimento del Farmaco , Rome , Italy .
authors.forename: Stefano
authors.initials: S
authors.lastname: Pieretti
authors.affiliation: c Istituto Superiore di Sanità, Dipartimento del Farmaco , Rome , Italy .
authors.forename: Francesca
authors.initials: F
authors.lastname: Marzoli
authors.affiliation: c Istituto Superiore di Sanità, Dipartimento del Farmaco , Rome , Italy .
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Fidanza
authors.affiliation: d Dipartimento di Farmacia , Università di Chieti-Pescara "G. d'Annunzio" , Chieti , Italy .
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
authors.affiliation: e Department of Biochemistry , Islamic Azad University , Sanandaj , Iran .
authors.forename: Sako
authors.initials: S
authors.lastname: Mirzaie
authors.affiliation: d Dipartimento di Farmacia , Università di Chieti-Pescara "G. d'Annunzio" , Chieti , Italy .
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.affiliation: f Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council , Naples , Italy .
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.affiliation: f Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council , Naples , Italy .
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Sándor
authors.initials: S
authors.lastname: Benyhe
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zádor
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Edina
authors.initials: E
authors.lastname: Szűcs
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Ötvös
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Anna I
authors.initials: AI
authors.lastname: Erdei
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Reza
authors.initials: R
authors.lastname: Samavati
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Dvorácskó
authors.affiliation: g Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences , Szeged , Hungary , and.
authors.forename: Csaba
authors.initials: C
authors.lastname: Tömböly
authors.affiliation: h Dipartimento di Farmacia , Università di Napoli "Federico II" , Naples , Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000032:analysis*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013057:Spectrum Analysis / Q000379:methods; D014508:Urea / Q000032:analysis*
chemical_list: C000608309:4-anilidopiperidine; D000700:Analgesics; D002219:Carbamates; D010880:Piperidines; D014508:Urea
keywords: FAAH enzyme; Fentanyl; MAGL enzyme; opioids; pain