title: Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain.
abstract: Acids 9a-f as possible bivalent ligands designed as a structural combination of opioid mu-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.
authors.affiliation: Departments of Chemistry, and Biochemistry and Molecular Biophysics, University of Arizona, Tucson, AZ 85721, USA. vardanyr@email.arizona.edu
authors.forename: Ruben
authors.initials: R
authors.lastname: Vardanyan
authors.forename: Gokhale
authors.initials: G
authors.lastname: Vijay
authors.forename: Gary S
authors.initials: GS
authors.lastname: Nichol
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.forename: Isuru
authors.initials: I
authors.lastname: Kumarasinghe
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Todd
authors.initials: T
authors.lastname: Vanderah
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D007192:Indenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009197:Myenteric Plexus / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism; D017450:Receptors, Opioid, mu; D014649:Vas Deferens / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D016861:Cyclooxygenase Inhibitors; D007192:Indenes; D007210:Indoleacetic Acids; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C093581:indene; D011451:Prostaglandin-Endoperoxide Synthases