title: Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration.
abstract: Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.
authors.affiliation: Novartis Institutes for BioMedical Research, 5 Gower Place, London, United Kingdom.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Dziadulewicz
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Bevan
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Brain
authors.forename: Paul R
authors.initials: PR
authors.lastname: Coote
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Culshaw
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Davis
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Edwards
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: Alyson J
authors.initials: AJ
authors.lastname: Fox
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.forename: Alex
authors.initials: A
authors.lastname: Groarke
authors.forename: Terance W
authors.initials: TW
authors.lastname: Hart
authors.forename: Werner
authors.initials: W
authors.lastname: Huber
authors.forename: Iain F
authors.initials: IF
authors.lastname: James
authors.forename: Adam
authors.initials: A
authors.lastname: Kesingland
authors.forename: Luigi
authors.initials: L
authors.lastname: La Vecchia
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Loong
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lyothier
authors.forename: Kara
authors.initials: K
authors.lastname: McNair
authors.forename: Cathal
authors.initials: C
authors.lastname: O'Farrell
authors.forename: Marcus
authors.initials: M
authors.lastname: Peacock
authors.forename: Robert
authors.initials: R
authors.lastname: Portmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schopfer
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yaqoob
authors.forename: Jiri
authors.initials: J
authors.lastname: Zadrobilek
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C524107:naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone; D000242:Cyclic AMP