Norbormide

Formula: C33H25N3O3

A manufactured toxic substance specifically toxic to rats

Source

  • Chemically engineered/manufactured

Biotransformation 6

  • The mechanisms involved in the effects of NRB have yet to be clarified
  • Three potential physiological pathways of activity lead to death
    1. Selective vasoconstriction of small blood vessels elicits divergent tissue responses, causing vasoconstriction of small arteries and vasodilation of large blood vessels in the rat, while dilating both small and large blood vessels of other species
    2. A previously unknown deleterious effect on mitochondrial function which was recently attributed to stimulation of the mitochondrial permeability transition
    3. Cardiotoxicity/coronaroconstriction

Toxicokinetics 2, 4

  • In more than three dozen species of mammals (including other rodents), birds, and fish, norbormide was found to be nonlethal at doses 20-200 times the LD50 in rats
  • Table 3 below outlines the effects of oral norbormide in mammals and birds from an early 1965 study conducted by Adolph P. Roszkowski

Carcinogenicity

  • No evidence or data

Mechanism of Action 1

  • Species specific action of opening the permeability transition pores in rat mitochondria
  • Calcium channel blocker & vasoconstrictor
  • NRB displays unique species-specific constrictor activity that is restricted to the peripheral arteries of the rat
  • In arteries from all other species tested, as well as in rat aorta and extravascular smooth muscle tissue, NRB exhibits vasorelaxant properties at concentrations that induce vasoconstriction in the rat peripheral arteries

Target organ

  • Peripheral rat arterioles

Signs and symptoms of toxicity 3, 5

  • As an acute poison, NRB has a rapid onset of action with toxic symptoms being recorded almost immediately
  • Rats administered norbormide were observed hunching, followed by hindlimb locomotor difficulties and weakness. This progressed to struggling, dyspnea, mild seizures, then death
  • Death occurs within 15 minutes to 4 hours due to vasoconstriction of peripheral arteries

Treatments

  • Human subjects who have ingested norbormide experience a transient decrease in blood pressure and temperature
  • Charcoal administration can be done, although due to normbormide’s lack of lethality in species other than rats, no treatment is warranted

References

  1. Fernanda Ricchelli, Federica Dabbeni-Sala, Valeria Petronilli, Paolo Bernardi, Brian Hopkins, Sergio, Bova, Species-specific modulation of the mitochondrial permeability transition by norbormide, Biochimica et Biophysica Acta (BBA) – Bioenergetics, Volume 1708, Issue 2, 2005, Pages 178-186, ISSN 0005-2728, https://doi.org/10.1016/j.bbabio.2005.03.002.
    (https://www.sciencedirect.com/science/article/pii/S0005272805000848)
  2.  G. I. Poos, R. J. Mohrbacher, E. L. Carson, V. Paragamian, B. M. Puma, C. R. Rasmussen, and A. P. Roszkowski. Structure-Activity Studies with the Selective Rat Toxicant Norbormide. Journal of Medicinal Chemistry 1966 9 (4), 537-540 DOI: 10.1021/jm00322a021
  3. Rennison D, Laita O, Bova S, et al. Design and synthesis of prodrugs of the rat selective toxicant norbormide. Bioorg Med Chem. 2012;20(13):3997-4011. doi:10.1016/j.bmc.2012.05.014
  4. Roszkowski AP. The pharmacological properties of norbormide, a selective rat toxicant. J Pharmacol Exp Ther. 1965;149(2):288-299.
  5. JoDrugs. NORBORMIDE. (n.d.). JoDrugs. Retrieved 05–28, from http://www.jodrugs.com/toxicologies/3169-norbormide.aspx
  6. Rennison, David et al. “Synthesis and activity studies of analogues of the rat selective toxicant norbormide.” Bioorganic & medicinal chemistry vol. 15,8 (2007): 2963-74. doi:10.1016/j.bmc.2007.02.012