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.

Separation, characterisation and biological evaluation of the individual isomers of the rat selective toxicant norbormide – isolated using a chemical derivatization strategy

“…In parallel, work continued on developing a strategy which would ultimately enable the isolation of the individual isomers of NRB, on a scale sufficient for extended in vivo biological evaluation. Previous studies working with NRB derivatives 16,17 had revealed that chromatographic differentiation between the isomers could be achieved through the installation of a group on the N-dicarboximide nitrogen. Employing a chemical derivatization strategy largely built on established literature protecting group chemistry, a selection of novel N-dicarboximide derivatives of NRB were synthesized in an effort to induce greater differentiation between the isomers during chromatographic separation.…”

“…[10][11][12] Although efforts to address this palatability problem using microencapsulation technologies have had varying degrees of success, the onset of symptoms has yet to be sufficiently delayed to significantly improve palatability, 13,14 and the potential for sub-lethal dosing remains a major hurdle. More recently, a prodrug approach [15][16][17] revealed a series of NRB derivatives which were demonstrated to be more palatable/efficacious to rats.…”

The Enigma of Norbormide, a Rattus-Selective Toxicant

“…To delay the onset of symptoms and circumvent the bait shyness problem (see above), numerous prodrugs of NRB have been developed. In cage trials, bait containing endo NRB prodrug 6 (Figure 7) was demonstrated to be more palatable to Sprague Dawley rats than bait containing unmodified NRB [16]. Moreover, 100% mortality was recorded (n = 12) versus 25% for unmodified NRB (n = 12).…”

“…A later attempt by Nadian and Lindblom [15], using gelatine microspheres over-coated with either shellac resin or an equal mixture of shellac and Eudragit RS ® , substantially achieved the desired delay in the delivery of a lethal dose of NRB, though its release through mastication in feeding trials remained an issue. More recent attempts to improve NRB palatability include the development of either prodrug derivatives, which require cleavage to the active form after consumption and absorption as a means of delaying the onset of symptoms [16], or novel formulations allowing the preliminary consumption necessary to deliver a lethal dose [17]. Both products tested in the field attained excellent results and are progressing through product development and registration in New Zealand and globally.…”

The potential of using Unmanned Aerial Vehicles (UAVs) for precision pest control of possums (Trichosurus vulpecula)

“…A new delivery method currently under development is woven flax packets/balls (flax bombs) containing toxin and coated in a thin layer of wax. Toxins currently undergoing registration include diphacinone/cholecalciferol mix for possums and norbormide for rats (Eason et al 2015;Choi et al 2016). Delivery of these toxins could be tested using flax bombs, and UAVs should provide a suitable delivery mechanism.…”