title: Fatty Acid-Derived Pro-Toxicants of the Rat Selective Toxicant Norbormide.
abstract: Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents and mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sublethal uptake and accompanying bait shyness. A series of NRB-derived pro-toxicants (3a - i, 4a - i, and 5a - i) were prepared in an effort to 'mask' this acute response and improve both palatability and efficacy. Their synthesis, in vitro biological evaluation (vasocontractile response in rat vasculature, stability in selected rat media) and palatability/efficacy in Sprague-Dawley, wild Norway, and wild ship rats is described. Most notably, pro-toxicant 3d was revealed to be free of all pre-cleavage vasoconstrictory activity in rat caudal artery and was subsequently demonstrated to release NRB in the presence of rat blood, liver, and pancreatic enzymes. Moreover, it consistently displayed a high level of acceptance by rats in a two-choice bait-palatability and efficacy trial, with accompanying high mortality. On this evidence, fatty acid ester prodrugs would appear to offer a promising platform for the further development of NRB-derived toxicants with enhanced palatability and efficacy profiles.
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: Hans
authors.initials: H
authors.lastname: Choi
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: Daniel
authors.initials: D
authors.lastname: Conole
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: Darcy J
authors.initials: DJ
authors.lastname: Atkinson
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: Olivia
authors.initials: O
authors.lastname: Laita
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: Morgan
authors.initials: M
authors.lastname: Jay-Smith
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Mario Angelo
authors.initials: MA
authors.lastname: Pagano
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ribaudo
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavalli
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.affiliation: Landcare Research, Canterbury Agriculture and Science Centre, Lincoln, New Zealand.
authors.forename: Brian
authors.initials: B
authors.lastname: Hopkins
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland, New Zealand.
authors.forename: David
authors.initials: D
authors.lastname: Rennison
mesh_terms: D000818:Animals; D008297:Male; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000473:pathology; D009636:Norbornanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D011355:Prodrugs / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D009636:Norbornanes; D011355:Prodrugs; C005321:norbormide
keywords: Esterase; Lipase; Norbormide; Prodrug; Rat toxicant; Rodenticide