title: Optimisation of the anti-Trypanosoma brucei activity of the opioid agonist U50488.
abstract: Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC(50) value of 59 nM as determined in our T. brucei in vitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound.
authors.affiliation: Drug Discovery Unit, College of Life Sciences, James Black Centre, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Smith
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.forename: Andrew
authors.initials: A
authors.lastname: Woodland
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.forename: Iain T
authors.initials: IT
authors.lastname: Collie
authors.forename: N Yi
authors.initials: NY
authors.lastname: Mok
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009292:Narcotic Antagonists; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer