Abstract:
Present day rodenticides, in the form of sub-chronic, acute and anticoagulant poisons, are used to control the ever-increasing rat problem worldwide. However, most share the common disadvantage of being non-specific broad-spectrum rodenticides leading to the increased risk of secondary poisoning. Norbormide NRB [5-(α - hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene- 2,3-dicarboximide], discovered in 1964 by Roszkowski et. al, was found to be uniquely species-specific towards rats and relatively harmless to all other species. NRB displays constrictor activity in rat peripheral arteries and elicits vasodilation of rat aorta and extravascular smooth muscle, whereas in all other species studied, NRB exhibits vasorelaxant properties only. However, one major drawback of NRB as a viable rodenticide relates to an evolutionary aversion developed by the rat leading to sub-lethal dosing due to either the unpleasant 'taste' or the rapid onset of effects. To date, efforts to mask this acute response in the form of microencapsulation have failed. Successful attempts at synthesizing prodrugs of NRB have been made within this research, with particular focus on the derivatization of the dicarboximide moiety in the form of N-(α- acyloxymethyl)imide esters of NRB. In vitro studies revealed a selection of non-vasoconstricting prodrugs. The discovery of alcohol 114, an analogue of NRB, exhibiting levels of efficacy as a vasoconstrictor of rat peripheral artery equal to that of NRB, was also made. Prodrug Families of both NRB and alcohol 114 were prepared and evaluated for their vasoconstrictory activity pre-cleavage, with those devoid of such effects undergoing in-house in vitro stability studies against rat blood and liver enzymes. The most promising candidates were subsequently assessed in vivo. NRB prodrug 83 was found to be devoid of all vasoconstrictory activity pre-cleavage, stable to oral administration and adequately susceptible to hydrolysis upon entering blood-circulation, releasing NRB at levels sufficient to elicit rapid death in rats. N-(2-hydroxyethyl)imide prodrug 159 provides an example of a para-substituted cinnamate with the capacity to elicit NRB-like death upon oral administration, with a lag time in the region of 1 hour. Extended rat feeding trials featuring 83 and 159 are to be undertaken in the future.