Toxicodynamics of Methemoglobin (MtHb) Inducers

Abstract

There is a need in New Zealand for a new, more advanced generation of toxins to minimize the impact of invasive animals. A new pest control agent, para-aminopropiophenone (PAPP), represents a lead candidate presently undergoing registration for the humane control of stoats and feral cats. It exhibits low toxicity to most bird species, no secondary poisoning risk, and has a simple and highly effective antidote. PAPP induces methemoglobinemia (MtHb), which acts to prevent oxygen from binding to red blood cells. This reduces oxygen supply to the brain, causing animals to become lethargic, sleepy, and unconscious prior to eventual death in 1 to 2 hours. Despite such promise, to date no previous study has comprehensively examined the effect of modifying the structure of PAPP on MtHb induction. Using PAPP as a platform, this paper describes the design, synthesis, and bioevaluation of PAPP-like red blood cell toxins. The impacts of introducing groups of varying electronic nature at different positions on the PAPP molecule are presently being evaluated. Analogues are synthesized and their MtHb-inducing properties determined using an in vitro assay to establish a formal structure-activity profile. In vivo evaluation in rats is used to assess both their acute toxicity and humaneness of potential candidates. Structure-activity profiles are discussed with the objective of optimizing the bioavailability and potency of PAPP-like compounds to target, high priority pests, particularly rodents.