3-Quinuclidinyl benzilate

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3-Quinuclidinyl benzilate
Bonding model 3-quinuclidinyl benzilate.svg
Bonding model
Ball and stick model 3-Quinuclidinyl-benzilate-balls.png
Ball and stick model
Names
IUPAC name
1-azabicyclo[2.2.2]octan-3-yl hydroxy(diphenyl)acetate
Other names
BZ
EA-2277
CS-4030
QNB
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.164.060 OOjs UI icon edit-ltr-progressive.svg
MeSH Quinuclidinyl+benzilate
PubChem CID
UNII
  • InChI=1S/C21H23NO3/c23-20(25-19-15-22-13-11-16(19)12-14-22)21(24,17-7-3-1-4-8-17)18-9-5-2-6-10-18/h1-10,16,19,24H,11-15H2 Yes check.svgY
    Key: HGMITUYOCPPQLE-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C21H23NO3/c23-20(25-19-15-22-13-11-16(19)12-14-22)21(24,17-7-3-1-4-8-17)18-9-5-2-6-10-18/h1-10,16,19,24H,11-15H2
    Key: HGMITUYOCPPQLE-UHFFFAOYAEb l
  • O=C(C(C1=CC=CC=C1)(C2=CC=CC=C2)O)OC3CN4CCC3CC4
Properties
C21H23NO3
Molar mass 337.419 g·mol−1
AppearanceWhite crystalline powder
Melting point 164 to 165 °C (327 to 329 °F; 437 to 438 K)
Boiling point 322 °C (612 °F; 595 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

3-Quinuclidinyl benzilate (QNB) (IUPAC name 1-azabicyclo[2.2.2]octan-3-yl hydroxy(diphenyl)acetate; US Army code EA-2277; NATO code BZ; Soviet code Substance 78 [1] ) is an odorless and bitter-tasting military incapacitating agent. [2] BZ is an antagonist of muscarinic acetylcholine receptors whose structure is the ester of benzilic acid with an alcohol derived from quinuclidine.

Contents

Physiochemical characteristics

BZ is a white crystalline powder with a bitter taste. It is odorless and nonirritating with delayed symptoms several hours after contact. [2] [3] It is stable in most solvents, with a half-life of three to four weeks in moist air; even heat-producing munitions can disperse it. It is extremely persistent in soil and water and on most surfaces. BZ is soluble in water, soluble in dilute acids, trichloroethylene, dimethylformamide, and most organic solvents, and insoluble with aqueous alkali. [3] [4]

Effects

As a powerful anticholinergic agent, BZ produces a syndrome of effects known as the anticholinergic toxidrome: these include both psychological and physiological effects, with the most incapacitating effect being a state of delirium characterized by cognitive dysfunction, hallucinations, and inability to perform basic tasks. The usual syndrome of physical anticholinergic effects are also present, including mydriasis (potentially to the point of temporary blindness), tachycardia, dermal vasodilation, xerostomia and hyperthermia. [5] The readily-observable symptoms of the anticholinergic toxidrome are famously characterized by the mnemonic "Mad as a hatter, red as a beet, dry as a bone and blind as a bat" (and variations thereof). [6]

Toxicity

Based on data from more than 500 reported cases of accidental atropine overdose and deliberate poisoning, the median lethal oral dose is estimated to be approximately 450 mg (with a shallow probit slope of 1.8). Some estimates of lethality with BZ have been grossly erroneous, and ultimately the safety margin for BZ is inconclusive due to lack of human data at higher dosage ranges, though some researchers have estimated it to be 0.5 to 3.0 mg/kg and an LD01 is 0.2 to 1.4 mg/kg (Rosenblatt, Dacre, Shiotsuka, & Rowlett, 1977). [7]

Treatment

Antidotes for BZ include 7-MEOTA, which can be administered in tablet or injection form. Atropine and tacrine (THA) have also been used as treatments, THA having been shown to reduce the effects of BZ within minutes. [8] [9] Some military references suggest the use of physostigmine to temporarily increase synaptic acetylcholine concentrations. [2]

History

Invention and research

BZ was invented by the Swiss pharmaceutical company Hoffman-LaRoche in 1951. [10] The company was investigating anti-spasmodic agents, similar to tropine, for treating gastrointestinal ailments when the chemical was discovered. [10] It was then investigated for possible use in ulcer treatment, but was found unsuitable. At this time the United States military investigated it along with a wide range of possible nonlethal, psychoactive and psychotomimetic incapacitating agents including psychedelic drugs such as LSD and THC, dissociative drugs such as ketamine and phencyclidine, potent opioids such as fentanyl, as well as several glycolate anticholinergics. [11] [12] By 1959, the United States Army showed significant interest in deploying it as a chemical warfare agent. [10] It was originally designated "TK", but when it was standardized by the Army in 1961, it received the NATO code name "BZ", the Chemical Corps initially referred to BZ as CS4030, then later as EA 2277. [7] [10] The agent commonly became known as "Buzz" because of this abbreviation and the effects it had on the mental state of the human volunteers intoxicated with it in research studies at Edgewood Arsenal in Maryland. [10] As described in retired Army psychiatrist James Ketchum's autobiographical book Chemical Warfare: Secrets Almost Forgotten (2006), work proceeded in 1964 when a general envisioned a scheme to incapacitate an entire trawler with aerosolized BZ; this effort was dubbed Project DORK. [13] BZ was ultimately weaponized for delivery in the M44 generator cluster and the M43 cluster bomb, until all such stocks were destroyed in 1989 as part of a general downsizing of the US chemical warfare program.

In 2022 a documentary film, Dr Delirium and The Edgewood Experiments, was broadcast on Discovery+, featuring an interview with Ketchum not previously shown. [14]

Use and alleged use

In February 1998, the British Ministry of Defence accused Iraq of having stockpiled large amounts of a glycolate anticholinergic incapacitating agent known as ‘Agent 15’. [15] Agent 15 is an alleged Iraqi incapacitating agent that is likely to be chemically identical to BZ or closely related to it. Agent 15 was reportedly stockpiled in large quantities prior to and during the Persian Gulf War. However, after the war the CIA concluded that Iraq had not stockpiled or weaponized Agent 15. [lower-alpha 1] [17]

According to Konstantin Anokhin, professor at the Institute of Normal Physiology in Moscow, BZ was the chemical agent used to incapacitate terrorists during the 2002 Nord-Ost siege, but at least 115 hostages perished due to overdose; [18] but many other agents have also been proposed, and none definitively confirmed.

In January 2013, an unidentified U.S. administration official, referring to an undisclosed U.S. State Department cable, claimed that "Syrian contacts made a compelling case that Agent 15, a hallucinogenic chemical similar to BZ, [19] was used in Homs". [20] [21] However, in response to these reports a U.S. National Security Council spokesman stated,

The reporting we have seen from media sources regarding alleged chemical weapons incidents in Syria has not been consistent with what we believe to be true about the Syrian chemical weapons program. [17] [21]

Legality

BZ is listed as a Schedule 2 compound by the OPCW (Szinicz, 2005). [22]

See also

Footnotes

  1. ↑ "We assess that Iraq never went beyond research with Agent 15 – a hallucinogenic chemical similar to BZ – or any other psychochemical. Agent 15 became an issue after a 9 February 1998 British press release claimed that the UK had information, thought to be reliable, that Iraq had large quantities of this chemical agent in the 1980s. UNSCOM and intelligence information indicated that Iraq researched a number of psychochemicals, including Agent 15, BZ, and PCP; however, UNSCOM indicated it saw no evidence of Iraqi importation of large quantities, weaponization, procurement of militarily significant quantities of precursors, or industrial production of these agents." [16]

Related Research Articles

Incapacitating agent is a chemical or biological agent which renders a person unable to harm themselves or others, regardless of consciousness.

<span class="mw-page-title-main">Edgewood Arsenal human experiments</span> US military chemical warfare research

From 1948 to 1975, the U.S. Army Chemical Corps conducted classified human subject research at the Edgewood Arsenal facility in Maryland. The purpose was to evaluate the impact of low-dose chemical warfare agents on military personnel and to test protective clothing, pharmaceuticals, and vaccines. A small portion of these studies were directed at psychochemical warfare and grouped under the prosaic title of the "Medical Research Volunteer Program" (1956–1975). The MRVP was also driven by intelligence requirements and the need for new and more effective interrogation techniques.

<span class="mw-page-title-main">Benzilic acid</span> Chemical compound

Benzilic acid is an organic compound with formula C
14H
12O
3 or (C
6H
5)2(HO)C(COOH). It is a white crystalline aromatic acid, soluble in many primary alcohols.

<span class="mw-page-title-main">Dimethylheptylpyran</span> Chemical compound

Dimethylheptylpyran is a synthetic analog of THC, which was invented in 1949 during attempts to elucidate the structure of Δ9-THC, one of the active components of Cannabis. DMHP is a pale yellow, viscous oil which is insoluble in water but dissolves in alcohol or non-polar solvents.

<i>N</i>-Methyl-3-piperidyl benzilate Chemical compound

N-Methyl-3-piperidyl benzilate is an anticholinergic drug related to the chemical warfare agent 3-quinuclidinyl benzilate.

<i>N</i>-Ethyl-3-piperidyl benzilate Chemical compound

N-Ethyl-3-piperidyl benzilate (JB-318) is an anticholinergic drug related to the chemical warfare agent 3-Quinuclidinyl benzilate.

<span class="mw-page-title-main">Ditran</span> Chemical compound

Ditran (JB-329) is an anticholinergic drug mixture, related to the chemical warfare agent 3-Quinuclidinyl benzilate (QNB).

<span class="mw-page-title-main">EA-3167</span> Anticholinergic deliriant drug

EA-3167 is a potent and long-lasting anticholinergic deliriant drug, related to the chemical warfare agent 3-quinuclidinyl benzilate (QNB) and to the bronchodilator drug tiotropium bromide. It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, in an attempt to develop non-lethal incapacitating agents. EA-3167 has identical effects to QNB, but is even more potent and longer-lasting, with an effective dose when administered by injection of as little as 2.5 μg/kg, and a duration of 120–240 hours. However unlike QNB, EA-3167 was never weaponized or manufactured in bulk.

<span class="mw-page-title-main">M43 BZ cluster bomb</span>

The M43 BZ cluster bomb, or simply M43 cluster bomb, was a U.S. chemical cluster bomb intended to deliver the incapacitating agent known as BZ. The weapon was produced in the early 1960s and all stocks of U.S. BZ were destroyed by 1989.

<span class="mw-page-title-main">Psychochemical warfare</span>

Psychochemical warfare — or "drug weapons" — involves the use of psychopharmacological agents with the intention of incapacitating an adversary through the temporary induction of hallucinations or delirium. These agents have generally been considered chemical weapons and, more narrowly, constitute a specific type of incapacitating agent. Although never developed into an effective weapons system, psychochemical warfare theory and research—along with overlapping mind control drug research—was secretly pursued in the mid-20th century by the US military and Central Intelligence Agency (CIA) in the context of the Cold War. These research programs were ended when they came to light and generated controversy in the 1970s. The degree to which the Soviet Union developed or deployed similar agents during the same period remains largely unknown.

<span class="mw-page-title-main">EA-3443</span> Chemical compound

EA-3443 is a potent and long lasting anticholinergic deliriant drug, related to the chemical warfare agent 3-Quinuclidinyl benzilate (QNB). It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, during research to improve upon the properties of earlier agents such as QNB.

<span class="mw-page-title-main">CAR-302,196</span> Chemical compound

CAR-302,196 is a moderately potent and relatively short lasting anticholinergic deliriant drug, related to the chemical warfare agent 3-Quinuclidinyl benzilate (QNB). It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, during research to improve upon the properties of earlier agents such as QNB.

<span class="mw-page-title-main">EA-3580</span> Chemical compound

EA-3580 is a potent anticholinergic deliriant drug with a fairly long duration of action, related to the chemical warfare agent 3-Quinuclidinyl benzilate (QNB). It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, during research to improve upon the properties of earlier agents such as QNB.

<span class="mw-page-title-main">CAR-226,086</span> Chemical compound

CAR-226,086 is a potent anticholinergic deliriant drug with a fairly long duration of action, related to the chemical warfare agent 3-quinuclidinyl benzilate (QNB). It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, during research to improve upon the properties of earlier agents such as QNB.

<span class="mw-page-title-main">EA-3834</span> Chemical compound

EA-3834 is a potent anticholinergic deliriant drug with a fairly long duration of action, related to the chemical warfare agent 3-quinuclidinyl benzilate (QNB). It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, during research to improve upon the properties of earlier agents such as QNB.

<span class="mw-page-title-main">CAR-301,060</span> Chemical compound

CAR-301,060 is a potent and long lasting anticholinergic deliriant drug, related to the chemical warfare agent 3-Quinuclidinyl benzilate (QNB). It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, during research to improve upon the properties of earlier agents such as QNB.

James Sanford Ketchum was a psychiatrist and U.S. Army Medical Corps officer who worked for almost a decade (1960–1969) on the U.S. military’s top secret psychochemical warfare program at the Edgewood Arsenal, Maryland, which researched chemicals to be used to "incapacitate the minds" of adversaries.

<span class="mw-page-title-main">CS-27349</span> Chemical compound

CS-27349, or L-2-α-tropinyl benzilate, is an experimental incapacitating agent. It acts as an antagonist to muscarinic acetylcholine receptors, causing delirium. It has 37% of the potency of the related compound 3-quinuclidinyl benzilate (BZ) in producing peripheral effects, but 85% of the potency in producing central effects. The mean dose required to incapacitate subjects was 1.2 times that of BZ. It has not been in use since the 1970s, and there have been no publications about its effects or long-term toxicology since then.

<span class="mw-page-title-main">CAR-302,282</span> Delirant drug

CAR-302,282 (302282, NSC-263548, α-(3-Methylbut-1-yn-3-enyl)mandelic acid 1-methyl-4-piperidyl ester) is an anticholinergic deliriant drug, invented under contract to Edgewood Arsenal in the 1960s. It is a potent incapacitating agent with an ED50 of 1.2μg/kg and a high central to peripheral effects ratio, and a relatively short duration of action compared to other similar drugs of around 6-10 hours. Despite its favorable properties it was relatively little researched compared to more high profile compounds from the series such as EA-3167 and EA-3580.

<span class="mw-page-title-main">CAR-302,668</span> Chemical compound

CAR-302,668 (302668, α-isopropylmandelic acid (1-methyl-1,2,3,6-tetrahydro-4-pyridyl)methyl ester) is an anticholinergic deliriant drug, invented under contract to Edgewood Arsenal in the 1960s. It is a reasonably potent incapacitating agent with an ED50 of 4μg/kg and a long duration of action of around 16-24 hours.

References

  1. ↑ Conant, Eve (22 November 2002). "More Questions Than Answers". Newsweek. Retrieved 15 April 2018.
  2. 1 2 3 QNB: Incapacitating Agent. Emergency Response Safety and Health Database. National Institute for Occupational Safety and Health. Accessed April 20, 2009.
  3. 1 2 Gupta, Ramesh C. (21 January 2015). Handbook of toxicology of chemical warfare agents (Second ed.). London: Academic Press. p. 152. ISBN   978-0-12-800494-4. OCLC   903965588.
  4. ↑ US Army FM 3-9
  5. ↑ Committee on Acute Exposure Guideline Levels; Committee on Toxicology; Board on Environmental Studies and Toxicology; Division on Earth and Life Studies; National Research Council. Washington (DC): National Academies Press (US); 2013 Apr 26.
  6. ↑ Ramjan KA; Williams AJ; Isbister GK; Elliott EJ (November 2007). "'Red as a beet and blind as a bat' Anticholinergic delirium in adolescents: lessons for the paediatrician". Journal of Paediatrics and Child Health. 43 (11): 779–780. doi:10.1111/j.1440-1754.2007.01220.x. PMID   17924941. S2CID   37914161.
  7. 1 2 Goodman, Ephraim (2010). Historical contributions to the human toxicology of atropine : behavioral effects of high doses of atropine and military uses of atropine to produce intoxication. Wentzville, Missouri: Eximdyne. p. 62. ISBN   978-0-9677264-3-4. OCLC   858939565.
  8. ↑ Gupta, Ramesh C. (21 January 2015). Handbook of toxicology of chemical warfare agents (Second ed.). London: Academic Press. p. 156. ISBN   978-0-12-800494-4. OCLC   903965588.
  9. ↑ Goodman, Ephraim (2010). Historical contributions to the human toxicology of atropine: behavioral effects of high doses of atropine and military uses of atropine to produce intoxication. Wentzville, Missouri: Eximdyne. p. 72. ISBN   978-0-9677264-3-4. OCLC   858939565.
  10. 1 2 3 4 5 Kirby, Reid. "Paradise Lost: The Psycho Agents", The CBW Conventions Bulletin, May 2006, Issue no. 71, pp. 2-3, accessed December 11, 2008.
  11. ↑ Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. (1984)
  12. ↑ Ketchum - Chemical Warfare: Secrets Almost Forgotten Archived 2022-10-22 at the Wayback Machine (2006)
  13. ↑ "Army's Hallucinogenic Weapons Unveiled". Wired. April 2007. Archived from the original on 24 December 2016. Retrieved 22 August 2022.
  14. ↑ Simonpillai, Radheyan (9 June 2022). "'It affected a great number of people': inside the world of shocking military drug experiments". The Guardian.
  15. ↑ Colin Brown; Ian Burrel (10 February 1998). "Iraqi 'zombie gas' arsenal revealed" . The Independent . UK. Archived from the original on 2011-05-13.
  16. ↑ Chemical Warfare Agent Issues (Report). Intelligence Update. U.S. Central Intelligence Agency. April 2002. Archived from the original on 14 April 2019. Retrieved 28 January 2013.
  17. 1 2 Lewis, Jeffrey (25 January 2013). "Why everyone's wrong about Assad's zombie gas". Foreign Policy. Retrieved 28 January 2013.
  18. ↑ "Hostages given military's nerve gas antidote". The Guardian . 28 October 2002.
  19. ↑ "Iraqi Chemical Agents and Their Effects". Chemical Warfare Agent Issues (Report). Intelligence Update. U.S. Central Intelligence Agency. April 2002. Archived from the original on 2019-04-14. Retrieved 2013-01-19.
  20. ↑ Rogin, Josh (15 January 2013). "Secret State Department cable: Chemical weapons used in Syria". Foreign Policy The Cable. Retrieved 16 January 2013.
  21. 1 2 "U.S. plays down media report that Syria used chemical weapons". Reuters. 16 January 2013. Retrieved 28 January 2013.
  22. ↑ Valdez, Carlos A.; Leif, Roald N.; Hok, Saphon; Hart, Bradley R. (2017-07-25). "Analysis of chemical warfare agents by gas chromatography-mass spectrometry: methods for their direct detection and derivatization approaches for the analysis of their degradation products". Reviews in Analytical Chemistry. 37 (1). doi: 10.1515/revac-2017-0007 . ISSN   2191-0189. S2CID   103245582.
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