Structural analogs of huperzine A improve survival in guinea pigs exposed to soman

doi:10.1016/j.bmcl.2012.11.083

Bioorganic & Medicinal Chemistry Letters

Volume 23, Issue 5, 1 March 2013, Pages 1544-1547

https://doi.org/10.1016/j.bmcl.2012.11.083 Get rights and content

Abstract

Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (−)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (−)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2 × LD₅₀.

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Acknowledgments

This work was supported by the US Army Medical Research and Material Command (Contract number W81XWH-08-1-0201). H.G. would like to thank Dr. Werner Tückmantel for his critical proofreading of the manuscript.

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Alkaloids are amino acid–derived basic nitrogen-containing organic compounds, mainly restricted to the plant kingdom. In plants, alkaloids are synthesized and accumulated as noxious molecules in response to environmental modulations and biotic and abiotic stresses. Human history has always been fascinated and influenced by various plant-derived alkaloids used as potions, remedies, psychoactive drugs, central nervous system stimulants, or poisons. In various cellular and animal models, plant alkaloids have displayed various pharmacological and medicinal activities such as neuroprotective, antihypertensive, cardioprotective, anticancer, antiinflammatory, vasorelaxant, antiparasitic, antibacterial, antifungal, antiprotozoal, antipyretic, abortifacient, antidiabetic, and antitussive activities. The neuroprotective ability of alkaloids has been exerted against Alzheimer disease, Parkinson disease, Huntington disease, multiple sclerosis, anxiety, depression, cognitive impairment and dementia, neurotoxicity, cerebral ischemia, drug addiction and substance abuse, psychological disorders, epilepsy, autoimmune encephalomyelitis, brain cancer, and so on. Alkaloids are known modulators of different biochemical and molecular markers regulating a number of signal transduction pathways, which are attributed to their potential as disease-modifying agents against the complex nature of neurological disorders. Bioactivity-guided isolation of many neuroprotective alkaloids has supported the age-old folkloric use of alkaloid-containing botanicals depicted in traditional literature and in many pharmacopeia. Since synergism exists among phytochemicals, the structure–activity relationship in alkaloids administered alone, or in combination with other natural or synthetic drugs or as ingredient(s) in polyherbal formulations, may elucidate the underlying mode of action of plant alkaloids. However, very few structure–activity relationship studies have been conducted in relation to the neuroprotection offered by the alkaloids. The present work describes the origin of neuroprotective plant alkaloids together with their underlying mechanism as therapeutic agents depicted in vitro, in vivo, ex vivo, or in human clinical studies. Hence the enormous structural diversity provided by the Nature and lead-identifying strategies incorporated with modern integrated approaches such as robotic separation, metabolic engineering, synthetic biology, genetic sequencing, and structure–activity studies will lead to the synthetic optimization of alkaloids as disease-modifying agents.
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Citation Excerpt :
Yet, a combination of (+)/(−) isomers of lower toxicity improves survival and reduces behavioral abnormalities against 1.2 × LD50 of soman [8]. Also, recent huperzine A analogs were demonstrated to improve survival against 2 × LD50 of soman in guinea pigs [9]. Other pharmacological pretreatments have been implemented in Western and other armies with known limitations and/or potent adverse effects (for review see Masson, 2011 and van Helden, 2011) [10,11].
Acetylcholinesterase is the physiological target for acute toxicity of nerve agents. Attempts to protect acetylcholinesterase from phosphylation by nerve agents, is currently achieved by reversible inhibitors that transiently mask the enzyme active site. This approach either protects only peripheral acetylcholinesterase or may cause side effects. Thus, an alternative strategy consists in scavenging nerve agents in the bloodstream before they can reach acetylcholinesterase. Pre- or post-exposure administration of bioscavengers, enzymes that neutralize and detoxify organophosphorus molecules, is one of the major developments of new medical counter-measures. These enzymes act either as stoichiometric or catalytic bioscavengers.
Human butyrylcholinesterase is the leading stoichiometric bioscavenger. Current efforts are devoted to its mass production with care to pharmacokinetic properties of the final product for extended lifetime. Development of specific reactivators of phosphylated butyrylcholinesterase, or variants with spontaneous reactivation activity is also envisioned for rapid in situ regeneration of the scavenger.
Human paraoxonase 1 is the leading catalytic bioscavenger under development. Research efforts focus on improving its catalytic efficiency toward the most toxic isomers of nerve agents, by means of directed evolution-based strategies. Human prolidase appears to be another promising human enzyme. Other non-human efficient enzymes like bacterial phosphotriesterases or squid diisopropylfluorophosphatase are also considered though their intrinsic immunogenic properties remain challenging for use in humans. Encapsulation, PEGylation and other modifications are possible solutions to address this problem as well as that of their limited lifetime.
Finally, gene therapy for in situ generation and delivery of bioscavengers is for the far future, but its proof of concept has been established.
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^†: These authors contributed equally to this work.

^‡: Present address: Merrimack Pharmaceuticals, Inc., 1 Kendall Square, Suite B7201, Cambridge, MA 02139-1670, USA.

^§: Present address: Interdepartmental Center Biopharmanet_Tec, Universita’ degli Studi di Parma, Via G. P. Usberti 27, Parma, Italy.

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Structural analogs of huperzine A improve survival in guinea pigs exposed to soman

Abstract

Graphical abstract

Section snippets

Acknowledgments

Trends Pharmacol. Sci.

J. Neurol. Sci.

Adv. Clin. Chem.

Biochem. Biophys. Res. Commun.

Pharmacol., Biochem. Behav.

Neurosci. Lett.

Neurosci. Lett.

FEBS Lett.

Trends Pharmacol. Sci.

Neurosci. Lett.

Life Sci.

Neurotoxicology

Neuropharmacology

Chem. Biol. Interact.

J. Appl. Toxicol.

Drug Chem. Toxicol.