title: Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands.
abstract: Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited μ-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85719, USA. vardanyr@email.arizona.edu
authors.forename: Ruben
authors.initials: R
authors.lastname: Vardanyan
authors.forename: Vlad K
authors.initials: VK
authors.lastname: Kumirov
authors.forename: Gary S
authors.initials: GS
authors.lastname: Nichol
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Erika
authors.initials: E
authors.lastname: Liktor-Busa
authors.forename: David
authors.initials: D
authors.lastname: Rankin
authors.forename: Eva
authors.initials: E
authors.lastname: Varga
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; D001665:Binding Sites; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1