MMSL 2015, 84(1):2-41 | DOI: 10.31482/mmsl.2015.001
DUAL USE RESEARCH OF CONCERN: DERIVATIVES OF 3-QUINUCLIDINYL BENZILATE (BZ)Review article
- 1083 Jewell Road, Milan, MI 48160, USA
Dual Use Research of Concern (DURC) deals with the unintended consequences of research and development and is particularly acute in the area of drug development. The United States National Science Advisory Board for Biosecurity (NSABB) has defined DURC as "research that, based on current understanding, can be reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health, agriculture, plants, animals, the environment, or materiel" (1). One particular receptor antagonist and glycolate anticholinergic compound (BZ, QNB or 3-quinuclidinyl benzilate) was stockpiled by the United States as a non-lethal chemical weapon that incapacitates and severely degrades the capability of exposed individuals (2). Given time and medical treatment, combatants and non-combatants exposed to such incapacitating agents could recover without any long-term effects. The purpose of this review is to identify potential new and more potent incapacitating agents based on the structures of BZ or atropine using peer reviewed publications of new pharmaceutical agents. A number of peer reviewed studies have reported on compounds with effects observed at lower concentrations than or comparable to BZ suggesting that these compounds could also be developed as potential chemical incapacitating chemical warfare agents and represent good examples of the principal of Dual Use Research of Concern.
Keywords: Dual Use Research of Concern; BZ; QNB; 3-Quinuclidinyl Benzilate; incapacitating agents; chemical warfare; muscarinic acetylcholine receptor antagonists
Received: September 3, 2014; Revised: November 10, 2014; Published: March 6, 2015 Show citation
References
- US Government. (2012). http://www.phe.gov/s3/dualuse/Documents/us-policy-durc-032812.pdf Accessed 5-25-2014.
- Kirby, R. Paradise Lost: The Psycho Agents. CBW Conventions Bulletin. 2006, 71, 1-5.
- Harris, E.D. (2007) In Rappert, B. and McLeish, C. (eds.), A Web of Prevention: Biological Weapons, Life Sciences, And The Governance Of Research. Earthscan, London, UK, pp. 115-132.
- Library Of Congress, T. (1997) Chemical Weapons Convention, Treaty Number 103-21.
- OPCW. (2005 Updated). Organization for the Prohibition of Chemical Weapons
- Biel, J.H., Sprengeler, E.P., Leiser, H.A., Horner, J., Drukker, A. and Friedman, H.L. Antispasmodics. II. Derivatives of N-Substituted-3-piperidols. J Am Chem Soc. 1955, 77, 2250-2256.
Go to original source...
- Ketchum, J.S. (2012) Chemical Warfare: Secrets Almost Forgotten. AuthorHouse, Bloomington.
- Lillie, S.H., Hanlon, E., Kelly, J.M. and Rayburn, B.B. (2005) Potential Military Chemical/Biological Agents And Compounds. http://www.fas.org/irp/doddir/army/fm3-11-19.pdf Accessed 15-25-14.
- Misik, J., Vanek, J., Musilek, K. and Kassa, J. Cholinergic antagonist 3-quinuclidinyl benzilate - Impact on learning and memory in Wistar rats. Behav Brain Res, 266, 193-200.
Go to PubMed...
- Sternbach, L.H. and Kaiser, S. Antispasmodics. I. Bicyclic Basic Alcohols J Am Chem Soc. 1952, 74, 2215-2218.
Go to original source...
- Sternbach, L.H. and Kaiser, S. (1952) Antispasmodics. II Esters of Basic Bicyclic Alcohols. J Am Chem Soc. 1952, 74, 2219-2221.
Go to original source...
- Sternbach, L.H. and Kaiser, S. Antispasmodics. III Esters of Basic Bicyclic Alcohols and Their Quaternary Salts. J Am Chem Society. 1953, 75, 6068-6069.
Go to original source...
- Interdepartmental Political-Military Group. (1969) US Policy on Chemical and Biological Warfare and Agents (Unclassified): Report to the National Security Council. http://www2.gwu.edu/~nsarchiv/NSAEBB/NSAEBB58/RNCBW6a.pdf accessed May 23, 2014.
- Caulfield, M.P. and Birdsall, N.J.M. International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors. Pharm Rev. 1998, 50, 279-290.
- Role, L.W. and Berg, D.K. Nicotinic receptors in the development and modulation of CNS synapses. 1996 Neuron, 16, 1077-1085.
Go to original source...
Go to PubMed...
- Abrams, P., Andersson, K., Buccafusco, J.J., Chapple, C., Chet de Groat, W., Fryer, A.D., Kay, G., Laties, A., Nathanson, N.M., Pasricha, P.J. et al. (2006) Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006, 148, 565-578.
Go to original source...
Go to PubMed...
- Culp, D.J., Lug, W., Richardson, L.A., Watson, G.E. and Latchney, L.R. Both M1 and M3 receptor exocrine secretion by mucous acini. Am J Physiol Cell Physiol. 1996, 271, C1963-C1972.
Go to original source...
Go to PubMed...
- Watson, E.L., Abel, P.W., Dijulio, D., Zeng, W., Makoid, M., Jacobson, K.L., Potter, L.T. and Dowd, F.J. Identification of muscarinic receptor subtypes in mouse parotid gland. Am. J. Physiol. Cell Physiol. 1996, 271, C905-C913.
Go to original source...
Go to PubMed...
- Beroukas, D., Goodfellow, R., Hiscock, J., Jonsson, R., Gordon, T.P. and Waterman, S.A. (2002) Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjogren's syndrome. Lab Invest. 2002, 82, 203-210.
Go to original source...
Go to PubMed...
- So, I., Yang, D.K., Kim, H.J., Min, K.W., Kange, T.M., Kim, S.J., Kim, K.W., Partk, K.H., Jeon, J.H., Choi, K.H. et al. Five subtypes of muscarinic receptors are expressed in gastric smooth muscles of guinea pig. Exp Mol Med. 2003, 35, 46-52.
Go to original source...
Go to PubMed...
- Volpicelli, L.A. and Levey, A.I. Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Prog Brain Res. 2004, 145, 59-66.
Go to original source...
Go to PubMed...
- Woldemussie, E., Feldmann, B.J. and Chen, J. Characterization of muscarinic receptors in cultured human iris sphincter and ciliary smooth muscle cells. Exp Eye Res. 1993, 56, 385-392.
Go to original source...
Go to PubMed...
- Shade, D.L., Clark, A.F. and Pang, I.-H. Effects of muscarinic agents on cultured human trabecular meshwork cells. Exp Eye Res. 1996, 62, 201-210.
Go to original source...
Go to PubMed...
- Bymaster, F.P., Carter, P.A., Yamada, M., Gomeza, J., Wess, J., Hamilton, S.E., Nathanson, N.M., Mckinzie, D.L. and Felder, C.C. Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity. Eur J Neurosci. 2003, 17, 1403-1410.
Go to original source...
Go to PubMed...
- Matsui, M., Motomura, D., Karasawa, H., Fujikawa, T., Jiang, J., Komiya, Y., Takahashi, S. and Taketo, M.M. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci U.S.A. 2000, 97, 9579-9584.
Go to original source...
Go to PubMed...
- Hulme, E.C., Birdsall, N.J.M. and Buckley, N.J. Muscarinic receptor subtypes. Ann Rev Pharmacol Toxicol. 1990, 30, 633-673.
- Dhein, S., Van Koppen, C.J. and Brodde, O.-E. Muscarinic receptors in the mammalian heart. Pharmacol. Res. 2001, 44, 161-182.
Go to original source...
Go to PubMed...
- Kobilka, B.K. (2007) G protein coupled receptor structure and activation. Biochim Biophys Acta, 1768, 794-807.
Go to original source...
Go to PubMed...
- Kruse, A.C., Kobilka, B.K., Gautam, D., Sexton, P.M., Christopoulos, A. and Wess, J. Muscarinic acetylcholine receptors: novel opportunities for drug development. Nat Rev Drug Discov, 13, 549-560.
Go to PubMed...
- Waymire, J.C. (2014), Neuroscience Online. University of Texas Health Science Center at Houston, Houston.
- Moshiri, M., Darchini-Maragheh, E. and Balali-Mood, M. Advances in toxicology and medical treatment of chemical warfare nerve agents. Daru. 2012, 20, 1-24.
Go to original source...
Go to PubMed...
- Sevelova, L., Kuca, K., Krejcova, G. and Vachek, J. The therapeutic efficacy of oxime treatment in cyclosarin-poisoned mice pretreated with a combination of pyridostigmine benactyzine and trihexyphenidyl. J Appl Biomed. 2004, 2, 163-167.
Go to original source...
- McLaughlin, B., Rickels, K., Abidi, M. and Toro, R. Meprobamate-benactyzine (Deprol) and placebo in two depressed outpatient populations. Psychosomatics. 1969, 10, 73-81.
Go to original source...
Go to PubMed...
- Alexander, L. Chemotherapy of Depression: Use of Meprobamate Combined with Benactyzine (2-Diethylaminoethyl Benzilate) Hydrochloride. J Am Med Assoc. 1958, 166, 1019-1023.
Go to original source...
Go to PubMed...
- Berger, F.M., Hendley, C.D. and Lynes, T.E. (1956) Pharmacology of the psychotherapeutic drug benactyzine (beta-diethylaminoethyl benzilate hydrochloride). Proc Soc Exp Biol Med. 1956, 92, 563-566.
Go to original source...
Go to PubMed...
- Zinner, N., Gittelman, M., Harris, R., Susset, J., Kanellos, A. and Auerbach, S. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J. Urology. 2004, 171, 2311-2315.
Go to original source...
Go to PubMed...
- Baba, Y., Higuchi, M., Abe, H., Fukuyama, K., Onozawa, R., Uehara, Y., Inoue, T. and Yamada, T. Anti-cholinergics for axial symptoms in Parkinson's disease after subthalamic stimulation. Clinical Neurology Neurosurgery. 2012, 114, 1308-1311.
Go to original source...
Go to PubMed...
- Carranza-del Rio, J., Clegg, N.J., Moore, A. and Delgado, M.R. Use of trihexyphenidyl in children with cerebral palsy. Pediatric Neurology. 2011, 44, 202-206.
Go to original source...
Go to PubMed...
- Montuschi, P., Macagno, F., Valente, S. and Fuso, L. (2013) Inhaled muscarinic acetylcholine receptor antagonists for treatment of COPD. Current Med Chem. 2013, 20, 1464-1476.
- Prat, M., Fernández, D., Buil, A.M., Crespo, M.I., Casals, G., Ferrer, M., Tort, L., Castro, J., Monleón, J.M., Gavaldà, A. et al. Discovery of Novel Quaternary Ammonium Derivatives of (3 R)-Quinuclidinol Esters as Potent and Long-Acting Muscarinic Antagonists with Potential for Minimal Systemic Exposure after Inhaled Administration: Identification of (3 R)-3-{[Hydroxy (di-2-thienyl) acetyl] oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2. 2] octane Bromide (Aclidinium Bromide). J Med Chem. 2009, 52, 5076-5092.
Go to original source...
Go to PubMed...
- Abood, L.G., Ostfeld, A. and Biel, J.H. (1959) Structure-Activity Relationships of 3-Piperidyl Benzilates with Pschotogenic Properties. Archives internationales de pharmacodynamie et de thérapie, 120, 186-200.
Go to PubMed...
- Lars, J., Nilsson, G., Wagermark, J. and Dahlbom, R. Potential antiparkinsonism agents. Quinuclidinyl benzhydryl ethers. J. Med. Chem. 1969, 12, 1103-1105.
- Albanus, L. Central and Peripheral Effects of Anticholinergic Compounds. Acta Pharmacol Toxicol. 1970, 28.
Go to original source...
Go to PubMed...
- Abramson, F.B., Barlow, R.B., Franks, F.M. and Pearson, J.D.M. Relationships Between Chemical Structure And Affinity For Postganglionic Acetylcholine Receptors Of The Guinea-Pig Ileum. Br J Pharmacol. 1974, 51, 81-93.
Go to original source...
Go to PubMed...
- Abramson, F.B., Barlow, R.B., Mustafa, M.G. and Stephenson, R.P. Relationships between chemical structure and affinity for acetylcholine receptors. Br J Pharmacol. 1969, 37.
Go to original source...
Go to PubMed...
- Atkinson, E.R., McRitchie, D.D., Shoer, L.F., Harris, L.S., Archer, S., Aceto, M.D., Pearl, J. and Luduena, F.P. Parasympatholytic (anticholinergic) esters of the isomeric 2-tropanols. 1. Glycolates. J Med Chem. 1977, 20, 1612-1617.
Go to original source...
Go to PubMed...
- NRC, National Research Council, Committee on Toxicology, Board on Toxicology and Environmental Health Hazards and Assembly of Life Sciences. (1982) Possible Long Term Health Effects of Short Term Exposure to Chemical Agents, Volume 1 Anticholinesterases and Anticholinergics. National Academy of Press, Washington D.C.
- Eckelman, W.C., Grissom, M., Conklin, J., Rzeszotarski, W.J., Gibson, R.E., Francis, B.E., Jagoda, E.M., Eng, R. and Reba, R.C. In vivo competition studies with analogues of 3-quinuclidinyl benzilate. J Pharm Sci. 1984, 73, 529-534.
Go to original source...
Go to PubMed...
- Gibson, R.E., Rzeszotarski, W.J., Eckelman, W.C., Jagoda, E.M., Weckstein, D.J. and Reba, R.C. Differences in affinities of muscarinic acetylcholine receptor antagonists for brain and heart receptors. Biochem Pharmacol. 1983, 32, 1851-1856.
Go to original source...
Go to PubMed...
- Rzeszotarski, W.J., Gibson, R.E., Eckelman, W.C., Simms, D.A., Jagoda, E.M., Ferreira, N.L. and Reba, R.C. Analogues of 3-quinuclidinyl benzilate. J Med Chem. 1982, 25, 1103-1106.
Go to original source...
Go to PubMed...
- Cohen, V.I., Gibson, R.E. and Reba, R.C. Synthesis and structure-activity relationships of new muscarinic antagonists. J Pharm Sci. 1987, 76, 848-850.
Go to original source...
Go to PubMed...
- Baumgold, J., Cohen, V.I., Paek, R. and Reba, R.C. Muscarinic receptor subtype selectivity of novel heterocyclic QNB analogues. Life Sci. 1991, 48, 2325-2329.
Go to original source...
Go to PubMed...
- Saunders, J., Cassidy, M., Freedman, S.B., Harley, E.A., Iversen, L.L., Kneen, C., MacLeod, A.M., Merchant, K.J., Snow, R.J. and Baker, R. Novel quinuclidine-based ligands for the muscarinic cholinergic receptor. J Med Chem. 1990, 33, 1128-1138.
Go to original source...
Go to PubMed...
- Tejani-Butt, S.M., Luthin, G.R., Wolfe, B.B. and Brunswick, D.J. N-substituted derivatives of 4-piperidinyl benzilate: affinities for brain muscarinic acetylcholine receptors. Life Sci. 1990, 47, 841-848.
Go to original source...
Go to PubMed...
- Gibson, R.E., Schneidau, T.A., Gitler, M., Zeeberg, B. and Reba, R.C. Muscarinic receptor selectivities of 3-Quinuclidinyl 8-xanthenecarboxylate (QNX) in rat brain. Life Sci. 1994, 54, 1757-1765.
Go to original source...
- Bonner, T.I., Buckley, N.J., Young, A.C. and Brann, M.R. Identification of a family of muscarinic acetylcholine receptor genes. Science. 1988, 237, 527-532.
- Vogel, W.K., Mosser, V.A., Bulseco, D.A. and Schimerlik, M.I. Porcine m2 muscarinic acetylcholine receptor-effector coupling in Chinese hamster ovary cells. J Biol Chem. 1995, 270, 15485-15493.
Go to original source...
Go to PubMed...
- Lee, J., Paik, C.H., Kiesewetter, D.O., Park, S.G. and Eckelman, W.C. Evaluation of stereoisomers of 4-fluoroalkyl analogues of 3-quinuclidinyl benzilate in in vivo competition studies for the M1, M2, and M3 muscarinic receptor subtypes in brain. Nucl Med Biol. 1995, 22, 773-781.
Go to original source...