DARK classics in chemical neuroscience: atropine, scopolamine and

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DARK classics in chemical neuroscience: atropine, scopolamine and other anticholinergic deliriant hallucinogens Anton Lakstygal, Tatyana Kolesnikova, Sergey Khatsko, Konstantin Zabegalov, Andrey Volgin, Konstantin Demin, Vadim Shevyrin, Edina Wappler-Guzzetta, and Allan Kalueff ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00615 • Publication Date (Web): 19 Dec 2018 Downloaded from http://pubs.acs.org on December 20, 2018

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ACS Chemical Neuroscience

DARK classics in chemical neuroscience: atropine, scopolamine and other anticholinergic deliriant hallucinogens

Anton M. Lakstygal1, Tatiana O. Kolesnikova2, Sergey L. Khatsko2, Konstantin N. Zabegalov2, Andrey D. Volgin3, Konstantin A. Demin3,4, Vadim A. Shevyrin2, Edina A. Wappler-Guzzetta5 and Allan V. Kalueff6,7,8,9,10,11*

1Graduate 2Ural

School of Biology, St. Petersburg State University, St. Petersburg, Russia

Federal University, Ekaterinburg 620002, Russia

3Institute

of Experimental Medicine, Almazov National Medical Research Centre, Ministry of

Healthcare of Russian Federation, St. Petersburg, Russia 4Institute

of Translational Biomedicine (ITBM), St. Petersburg State University, St. Petersburg

199034, Russia 5

ZENEREI Research Center, Slidell LA 70458, USA

6School

of Pharmacy, Southwest University, Chongqing, 400700, China

7Anatomy

and Physiology Laboratory, Ural Federal University, Ekaterinburg, Russia

8Laboratory

of Biological Psychiatry, ITBM, St Petersburg State University, St Petersburg 199034,

Russia 9Scientific 10Granov

Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia

Russian Scientific Center of Radiology and Surgical Technologies, Ministry of Healthcare

of Russian Federation, St. Petersburg, Russia 11Almazov

National Medical Research Centre, Ministry of Healthcare of Russian Federation, St.

Petersburg, Russia *Corresponding author: Allan V. Kalueff, PhD School of Pharmacy, Southwest University, Chongqing, 400700, China Tel/Fax: +1-240-899-9571 Email: [email protected] Funding source: The research was supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851 to АVK. KAD is supported by RFBR grant 18-34-00996 and Special Rector’s Fellowship for SPSU PhD Students.

Conflict of interest: Authors declare no conflicts of interest. ACS Paragon Plus Environment

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Abstract:

Anticholinergic drugs based on tropane alkaloids, including atropine, scopolamine and hyoscyamine, have been used for various medicinal and toxic purposes for millennia. These drugs are competitive antagonists of acetylcholine muscarinic (M-) receptors that potently modulate the central nervous system (CNS). Currently used clinically to treat vomiting, nausea and bradycardia, as well as alongside other anesthetics to avoid vagal inhibition, these drugs also evoke potent psychotropic effects, including characteristic delirium-like states with hallucinations, altered mood and cognitive deficits. Given the growing clinical importance of anti-M deliriant hallucinogens, here we discuss their use and abuse, clinical importance, and the growing value in preclinical (experimental) animal models relevant to modeling CNS functions and dysfunctions.

Keywords: the cholinergic system, deliriant drugs, atropine, scopolamine, hallucinogens, antimuscarinic effects

Abbreviations: AS – anticholinergic syndrome, BBB – the blood-brain barrier, MDD – major depressive disorder, BDD – bipolar depressive disorder, CNS – central nervous system, DAT – dopamine transporter, DFSA - drug facilitating sexual assault, GABA – gamma-aminobutyric acid, M – muscarinic (receptors), PNS – peripheral nervous system, TCA – tricyclic antidepressant, MDMA – 3,4-methylenedioxymethamphetamine


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1. Introduction: chemistry and synthesis of deliriant anticholinergic agents Atropine, hyoscyamine and scopolamine (hyoscine, Fig. 1) are antagonists of the muscarinic (M) acetylcholine receptors that play an important role in modulating the central nervous system (CNS, Table 1). Chemically, they belong to tropane alkaloids, a group of over 200 analogs sharing a common tropane (N-methyl-8-azabicyclo[3.2.1]octane) fragment1-3. Structurally similar to acetylcholine, hyoscyamine and atropine are esters of tropine and optically active tropic acid. Pure biologically active hyoscyamine is a levorotatory optic isomer (S)-(–)-hyoscyamine and atropine is optically inactive (±)-racemate of hyoscyamine3, 4. Scopolamine is an optically and biologically active, racemation-stable (S)-(–)-isomer5 whose chemical structure, unlike atropine and hyoscyamine, includes the epoxy group in positions 6 and 7 of the tropane ring (Fig. 1). Atropine, scopolamine and hyoscyamine are most studied tropane alkaloids (Fig. 1, inset) naturally occurring in plants of the Solanaceae family (Anisodus, Anthocercis, Mandragora, Brugmansia, Duboisia, Hyoscyamus, Datura, Atropa, and Scopolia)1,

5-7.

Their alkaloid content

varies between 0.01–3%, depending on the species1, 5. Chemical names of these alkaloids originate from the respective plants from which they were extracted in the past. Atropine was extracted from Atropa belladonna (the deadly nightshade, belladonna) as the principally active compound by Mein and then – as a purified substance - by Runge3, 6, 8. The name ‘tropane’ itself originated from the Latin name for this plant2, 3, 8, also called ‘Atropos’ by the ancient Greeks9. Hyoscyamine was extracted from Hyoscyamus niger (the black henbane), and scopolamine from Scopolia carniolica (the henbane bell)2, 5, 10. Common street drug names of major tropane alkaloids are given in Table 2. The biosynthesis of tropane alkaloids occurs in roots, and then they are transported within the xylem1, 5. Since their chemical synthesis is complex and less feasible, plants remain the main source of tropane alkaloids5. Various Solanaceae plants accumulate pharmacologically active hyoscyamine and scopolamine as their major alkaloids, and are widely used for industrial production7, 11 as salts (after acidic/water treatment) or bases (following treatment with organic solvents like methanol, ethanol or chloroform)1. To isolate specific alkaloids, chromatography can also be used12. Furthermore, while plant cultivation is limited by ecological and climatic factors, it can be enhanced


4

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by hydroponic culturing and genetic engineering of alkaloid-producing plants and/or hairy root cultures1, 5, 7, 13-15. Enzymatic biosynthesis of tropane alkaloids involves amino acids L-ornithine, L- arginine (to form tropane ring) and L-phenylalanine (to produce tropic acid), as precursors1, 5, 7, 16-18 (Fig. 2). Ornithine undergoes enzymatic decarboxylation to produce putrescine, whereas arginine metabolism requires an additional step to form аgmatine and N-carbamoylputrescine. Putrescine is next methylated into N-methylputrescine, oxidatively desaminated into 4-(methylamino)butanal, which undergoes spontaneous cyclization into a reactive precursor of tropane ring, 1-methyl-3,4-dihydro2H-pyrrolium cation. Its reaction with acetoacetic acid generates 4-(1-methylpyrrolidin-2-yl)-3oxobutanoic acid, whose cyclization with decarboxylation produces tropinone (the first intermediate with the tropane ring). Reduction of its carbonyl group generates tropine which, in turn, reacts with phenyllactic acid (produced from phenylalanine) to generate littorine – a key precursor of hyoscyamine and other tropane alkaloids, whose 2-step reaction (via 6β-hydroxyhyoscyamine) produces scopolamine (Fig. 2). The first attempt to establish the structure of atropine was made by Kraut in 186319, detailing its degradation to tropine and tropic acid3. The full synthesis of atropine was reported by Willstätter in 190120 as a process that starts from cycloheptanone which undergoes a 8-step conversion into cycloheptatriene (Fig. 3). Sequential bromination of cycloheptatriene, replacing bromine with dimethylamine and reducing one of the two double links, results in 1-dimethylaminocyclohept-4-en3, 6, 18, 20,

followed by bromination of the remaining double link, creating a ring in 2-bromotropane salt

that produces tropidine upon reaction with bases. Tropane can then be produced in a 4-step reaction from tropidine3, 18, 20. Overall, albeit generally complex and low-yield, this atropine synthesis has been critical for proving its chemical structure. In 1917, a new efficient method was proposed by Robinson3,

6, 21,

based on 3-component condensation of succinaldehyde, methylamine and

acetonedicarboxylic acid (Fig. 3). Subsequent reduction of tropinone generates tropine, and its fusion with tropic acid in the presence of hydrogen chloride produces atropine3. This method of synthesis, with some modifications, remains widely used today3, 6, although alternative methods have also been proposed22-24, including continuous-flow synthesis25,

26.

Since scopolamine is a more expensive


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product than atropine6, chemical epoxidation of tropane ring may be considered. The first total synthesis of scopolamine from (–)-tropane-3α,6β-diol was described in 19597, and while alternative methods of scopolamine synthesis exist23, its chemical synthesis remains less than extraction from plants6. Benzatropine, a tropane ring-containing anti-Parkinson agent (Fig. 1), was synthesized via the diphenyldiazomethane reaction with tropine by Merck & Co, patented in USA in 1952, and appeared on the marked as a mesylate salt in 195427, 28 (Table 2; diphenyldiazomethane was later replaced with a more safer agent, diphenylhalomethane29). Laboratory combinatorial synthesis of benzatropine and its analogs via azidoether has also been described30. Biperiden (Fig. 1) is another structurally related agent synthesized in Germany in 195331, which was patented in USA in 195732 and appeared in the market in 195928 as a therapy for Parkinson’s disease (Table 2). Biperiden can be synthesized by Mannich's reaction from acetophenone, formaldehyde and piperidine hydrochloride, followed by treatment with the Grignard reagent prepared in diethyl ether by 5-chloro-2-norbornene reaction with magnesium shavings31, 32. A modern method of industrial synthesis of biperiden utilizes 5-ethylene2-norbornene, whose selective oxidation produces 5-acetyl norbornene, which enters into a Mannich's reaction with formaldehyde and piperidine hydrochloride, followed by reaction with phenylmagnesium bromide33. Containing a fragment of tropic acid (Fig. 1), tropicamide was approved in USA in 1959 as an ophthalmological drug28, originally developed in 1952 by Hoffmann-La Roche, Inc. (Switzerland) and patented in USA34, 35. Tropicamide was synthesized from N-(pyridin-4-ylmethyl)ethanamine, obtained from 4-(chloromethyl)pyridine and ethylamine reaction with chloroanhydride of 3-acetoxy2-phenylpropanoic acid, and subsequent acidic hydrolysis of the O-acetyl group34, 35 (also note a similar patented reaction using modern technological approach and reagents36). The same method was used for synthesis of enantiomers of tropicamide37. Two other anti-Parkinson drugs, trihexyphenidyl and procyclidine, appeared in the USA market in the 1950s28 (Table 2), both sharing a common 1-cyclohexyl-1-phenylpropanol moiety but different (piperidine or pyrrolidine) rings (Fig. 1). Trihexyphenidyl has been originally developed as a spasmolytic agent, and its synthesis has been described in research and patent literature in early ACS Paragon Plus Environment

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1950s38-42

via

Grignard

reaction

of

cyclohexylmagnesium

bromide

with

3-(1-

piperidino)propiophenone, which is in turn obtained through Mannich's reaction of acetophenone, formaldehyde and piperidine hydrochloride28, 39, 40. Using phenylmagnesium bromide as a Grignard reagent, and ethyl cyclohexyl ketone for Mannich’s reaction can also be possible40. Moreover, partial catalytic reduction of diphenyl alkanolamines39, 42, albeit complicated by purification steps43, can be used. To increase yield, trihexyphenidyl can be synthesized from 3-chloropropanoyl chloride through sequential Grignard reaction with cyclohexylmagnesium and phenylmagnesium bromides, and treating the tertiary alcohol with piperidine43 (see synthesis of trihexyphenidyl enantiomers in 44, 45). Early reports on procyclidine appeared in the 1950s39,

46,

and its synthesis resembles that of

trihexyphenidyl, using pyrrolidine as an amine instead of piperidine38-46. 2. History of use and abuse Tropane alkaloids have a long history of use and abuse, as their spiritual, medicinal and toxic properties have been known since antiquity47 (Fig. 4). For example, fertility-promoting effects of mandrake, a plant of the Mandragora genus, are mentioned in the Old Testament (Genesis 30:1422). Ancient warriors and assassins have often soaked their weapons in the extract of the deadly nightshade9. The Solanaceae plants have been widely used as a poison for political assassinations, including killing of Macbeth, Duncan and Roman Emperors Claudius and Augustus9. In Shakespeare’s “Hamlet”, his father was poisoned by an ear-drop prepared from henbane48. Folk medicine has been using tropane alkaloids for centuries as analgesic agents, hallucinogens and poisons, representing one of the most ancient plant-derived compounds known to man49. Apart from religious rituals, pre-Columbian American civilizations medicated asthma, rheumatism and anxiety with plants of the Datura genus, whereas in medieval Spain extracts from of the Solanaceae family plants have been used as both recreational drugs and poisons50. In some Middle Eastern countries, people continue to use Datura plants to treat musculoskeletal problems, such as limbs swelling51. In medieval time, Solanaceae plants have commonly been used by witches, who would often prepare Pharmaka diabolics - the ointment that caused mental alterations (e.g., feeling of flying) and stimulated sexual desires52. By the 16-17th centuries, the Solanaceae plants have also begun to interest herbalists and apothecaries for their therapeutic effects53. In the 18th century, extracts from ACS Paragon Plus Environment

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belladonna and other plants became a famous cosmetic ingredient used to enlarge pupils - a standard of female beauty at the time54 (hence is the plant name from Italian ‘bella donna’, a beautiful lady). More recently, tropane alkaloids have been widely utilized in physiology and pharmacology research. For instance, Schmiedeberg demonstrated that heart slowed by electrical stimulation returns to its normal rate after atropine exposure55. Later, the need to block sea sickness has drawn attention to clinical effects of tropane alkaloids – the line of research actively supported by the UK military and the Medical Research Council56. In the first half of the 20th century, atropine and scopolamine have been used as anesthetics, therapies for bradycardia, and to treat nausea and vomiting during seasickness57 or post-operative sickness58-60. Furthermore, atropine and other anti-M tropane alkaloids exert potent central nervous system (CNS) effects, including delirium-like and hallucinogenic effects (Table 1). This shared action has placed these drugs into a special group of deliriants hallucinogens61, 62

that evoke characteristic agitation, confusion, hallucinations and cognitive deficits63, 64 (Table 1,

Fig. 5). Atropine and scopolamine are the two best-studied anti-M deliriant agents (Table 3, Fig. 1). As they cause both central and peripheral M-mediated anticholinergic effects (Tables 1 and 4), their common action includes restlessness, excitement, hallucinations, euphoria, disorientation, stupor, coma or even death (typically, from respiratory depression). Scopolamine also produces rapid and robust antidepressant effects in unipolar and bipolar depression patients65, 66. At the same time, atropine, scopolamine and other deliriants can trigger anticholinergic syndrome (AS, Table 4), a critical diagnosis accounting for nearly 15000 toxic cases each year67. Even at therapeutic doses, patients on scopolamine are at risk for AS toxicity, especially when combined with other medications with anticholinergic effects. For example, beyond atropine and scopolamine, there are hundreds of unique pharmacological and herbal compounds that can cause anti-M effects68, such as antihistamines, tricyclic antidepressants (TCAs) and sleeping pills (e.g., doxylamine)69. Thus, both plant and synthetic anticholinergics have multiple therapeutic and side effects, and their clinical importance continues to grow (Fig. 1). Today, atropine is a controlled substance, currently listed in Schedule V in the US. Drugs from this schedule are the least regulated controlled substances, as they have a relatively low potential ACS Paragon Plus Environment

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for abuse and a currently accepted medicinal use. Scopolamine and hyoscyamine are not listed as controlled substances in the US. However, access to these three deliriant drugs is administratively limited, and prescriptions are needed for them in many countries worldwide. US researchers must have an approved state license to be able to explore atropine effects in vivo or in vitro, due to its current scheduling as a controlled substance. 3. Clinical and preclinical pharmacology Scopolamine is an M-receptor antagonist with peripheral and central anticholinergic, as well as sedative and amnestic properties (Table 1). In humans, scopolamine patches may evoke transient psychosis even without AS-like toxicity67. Fast-acting antidepressant effects of scopolamine have also been described70, with somewhat stronger action in women71. Scopolamine administration in randomized placebo–controlled study in patients with major depressive or bipolar disorders evokes antidepressant effects72, and scopolamine-containing drugs are efficient in panic attack, nervousness and anxiety73. Preclinical effects of scopolamine, recently discussed in-depth74 (Table 5), include cognitive impairments in passive avoidance task and Morris water maze75-77, poorer fear-context conditioning78 and increased anxiety-like behavior79. Atropine is another typical anti-M drug80. As a parasympathetic blocker, it reduces salivary and bronchial secretions, raises the heart rate and relaxes the smooth muscle of the urinary bladder, gastro-intestinal tract and bronchi81. Since atropine easily crosses the blood-brain barrier (BBB), it quickly causes CNS effects - restlessness, mental excitement/agitation and hallucinations (Table 1). While nerve gases used in warfare (e.g., Sarin) inactivate acetylcholinesterase82 and cause lethality, atropine acts as a potent antidote83 commonly used by the military84. Atropine also prevents accidental poisoning by organophosphate insecticides (which also inhibit acetylcholinesterase activity)85. In rodents, similarly to scopolamine (Table 4), atropine impairs newly formed fear memories86 and evokes anxiety74, 79. Atropine also acts as competitive antagonist of serotonin 5HT3 receptors87 and may modulate various neurotransmitters involved in emotionality (e.g., cholinergic, dopaminergic, glutamatergic and GABA-ergic)88 and behavior87. Benzatropine is an atypical anti-M tropane alkaloid (Table 3) which also inhibits the dopamine transporter (DAT)89, is used clinically to treat Parkinson’s symptoms90, and evokes ACS Paragon Plus Environment

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antihistaminic effects91. Several benzatropine analogs also inhibit histamine H1 receptors91 and DAT, predictably inducing reward-like effects (e.g., in primate models)92, 93. Procyclidine exerts strong antidotal anti-M, antiglutamatergic and antiepileptic effects94. It also reduces anxiety in depressed patients treated jointly with chlorpromazine and, to a lesser extent, with procyclidine alone95. However, it impairs learning and memory in both rodent96 and clinical studies97, and (similarly to other anticholinergic drugs) evokes strong delirium and visual hallucinations that are suppressed by anticholinesterase drugs98. Tropicamide is an anticholinergic tropic acid derivative with an anti-M activity, often causing mydriasis and cycloplegia99. While topical abuse of ophthalmic solutions has occurred previously, intravenous abuse of tropicamide has emerged as a recent medical problem100. Notably, some case reports suggest that tropicamide may improve subjective effects of heroin intake, causing a more powerful relief and relaxation (compared to heroin alone), but also AS-like blurred vision, dizziness, illusions and hallucinations, as well as memory- and appetite loss101. Furthermore, tropicamide also induces palpitations, dissociation, anxiety, and sweating in humans101, and suppresses some Parkinson-like phenotypes (e.g., stereotypic jaw movements) in rodents102. Biperiden is a predominantly M1-antagonist103 (Table 3) which impairs cognitive performance (verbal memory, visuospatial processes, and motor learning) clinically104 and disrupts short-term memory, but not sensorimotor responding, food motivation or attention, in rodents105. The most common central side-effects of biperiden are drowsiness, headache, vertigo and dizziness106 (Table 1). Its peripheral AS-like side effects include blurred vision, mydriasis, dry mouth, abdominal discomfort and constipation107, 108. Finally, trihexyphenidyl is an anti-M drug acting both centrally and peripherally109, and currently used to treat tremors, spasms, stiffness and muscle weakness in patients with Parkinson’s disease110 as well as in similar conditions evoked by some CNS drugs (e.g., fluphenazine, haloperidol and chlorpromazine)111. Like biperiden, trihexyphenidyl impairs memory in rats103 and worsens cognitive performance clinically112. 4. Metabolism and pharmacokinetics Atropine, scopolamine and hyoscyamine are usually taken orally, intravenously, intramuscularly or in the form of suppository, aerosols or transdermal patches68, ACS Paragon Plus Environment

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Low 10

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molecular weights of scopolamine (303 g/mol) and atropine (289 g/mol) and their lipophilic character enable an easy passing the gastric mucosa of humans and mammals after intake, ensuring their fast absorption and action116. The absorption of atropine and other tropane alkaloids through the skin is moderate115. The first signs of clinical atropine poisoning appear 15-30 min after ingestion; its halflife is 4 h, and 90% of the drug is excreted with urine within 24 h117. The peak plasma levels of atropine depend on the route of administration, ranging from 13 min for intramuscular to 1 h for oral and 1.5-4 h for aerosol administration118. Most of the drug effects disappear within 24-48 h117, except for mydriasis that can persist for days119. Scopolamine has a short half-life in plasma, peaking 30 min after ingestion120, but causing overt physiological effects lasting for hours. Bioavailability of hyoscyamine is approximately 43%. Its pharmacological effects and their duration depend on the form of the drug, appearing within minutes for tablets, solutions or elixirs (peaking at 15-60 min and lasting for 4 h) and within 20-30 min for capsules (peaking at 40-90 min and lasting for 12 h)121. The half-life of hyoscyamine is 3.5 h in serum and 7 h in plasma121. Hyoscyamine is distributed through the whole body, readily passing through organ barriers and in small quantities penetrating into breast milk121. Tropane alkaloids are metabolized in the liver and excreted with urine, with 13-50% atropine excreted unchanged, and ~65% scopolamine excreted within 24 h as glucuronide and sulfide conjugates122. Hyoscyamine is also metabolized in liver121, and is excreted with urine within 12 h, mostly unchanged123. Post-mortem concentrations of hyoscyamine can reach 0.2 mg/L in the blood and 14.2 mg/L in the urine124. Atropine (8-15 pg/mg) and scopolamine (1–1.3 pg/mg) can also be detected in hair125. The lethal concentration in the peripheral blood for atropine is 0.3 mg/L and for scopolamine 0.005 mg/L126. Procyclidine, trihexylphenyl, biperidine are typically administered as hydrochloride salts and are rapidly absorbed in the gastrointestinal tract, whereas benzatropine is used as a mesylate salt with a slower absorption. Plasma concentrations of these drugs peak within 2.5 h (7 h for benzatropine)127. Depending on the dose, maximal plasma concentrations after oral intake are 1.5 ng/ml for benzotropine128, 10-50 ng/ml for trihexyphenyl129, 130, 4 ng/mL for biperidine131 and 113 ng/ml for procyclidine132. Biperidine quickly penetrates BBB in rats, and its concentration in the brain peaks ACS Paragon Plus Environment

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within 3-10 min after an intravenous injection133 due to high lipophilicity of this drug. Fasting and change in the volume of adipose tissue in rats reduce biperidine accumulation134. In humans, biperedine plasma levels after an oral intake are lower than after intravenous injection, peaking at 1.5-2 h with the half-life of ~21 h. The bioavailability of biperidine is 33%, and it is excreted by kidneys and the liver131. Tropicamide is usually administered intravenously, and its physiological effect lasts for 0.5-6 h135. Data are currently limited on its metabolism and pharmacokinetics. Following an eye instillation, it absorbs rapidly, within 5 min reaching the peak plasma concentration, and disappears from the system within 2 h136. Following an oral administration in rats, the maximal concentration of the drug is detected in the stomach within 1-6 h, with much lower levels also found in the brain, lungs and spleen137. 5. Current social and cultural impact Plants containing anti-M deliriant tropane alkaloids have long been used in different cultures for the unique bodily and mental/spiritual experiences they evoke (Table 1, Fig. 4). While the use of tropane alkaloids for political poisoning or witchcraft is long gone, their societal impact remains high due to active medicinal use, severe toxicity, some abuse potential, robust deliriant/hallucinogenic properties and the availability of synthetic analogs (Fig. 1) with potent CNS action. For example, since antiquity, people have used belladonna and other plants for special beverages that bring people ‘closer to gods’ through ecstasy and dreaming52. The link between tropane alkaloid use and other drugs has also been long recognized. In Ancient Egypt, mandrake plant has been added to beer to potentiate alcohol action52. In Europe, torn apples and henbane were commonly utilized for this purpose138,

139.

Similar synergism occurs in pharmacotherapy, since some anticholinergic drugs

potentiate the effect of other agents (e.g., procyclidine increases antidepressant effects of chlorpromazine140), which can be used therapeutically but may also worsen side-effects. Although a generally unpleasant subjective experience with deliriant hallucinations and multiple AS-like side-effects (Tables 5 and 6) limit the appeal of these drugs, their abuse is possible. In modern history, the use and abuse of deliriants as psychoactive substances has been popular among some young people. For example, in the late 1960s, deliriant poisoning became widespread among USA students using asthma medicine ‘Asthmador’ (containing an extract of D. stramonium) to ACS Paragon Plus Environment

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experience delirium and hallucinations141. Anticholinergic drugs are abused in low- and middleincome countries (e.g., Saudi Arabia, Jordan, Iraq and Brazil), especially by young unemployed and marginalized people with polysubstance abuse and a family history of mental disorders142. A recent rise of abuse of anticholinergics reported in Europe involves poor African immigrants142. Such targeting of people on low income and welfare by anti-M deliriant drugs can be due to their low cost (vs. other psychoactive substances - cannabis, ‘ecstasy’/MDMA or cocaine)143, and easy access to them (due to weak control of anticholinergic drugs)142. Presently, the most commonly abused anticholinergic drug is trihexyphenidyl because of its strong euphorigenic effect144. Biperiden abuse also occurs among people who have previously abused other substances145. Albeit a less potent anticholinergic then trihexyphenidyl, it has a strong potential to abuse, causing various mood disorders and (upon withdrawal) dysphoria, fatigue, lack of motivation and insomnia142. Recently, scopolamine abuse has been noted in USA prisoners with prior history of abuse (mainly cocaine and heroin), using crushed scopolamine tablets for smoking146. Overall, the abuse of deliriants tends to occur in groups with high risk of social vulnerability, as only populations that do not have access to other drugs would become abusers of drugs that are toxic and induce unpleasant subjective effects. The high prevalence of abuse of such substances may therefore be more indictive of socioeconomic status of the individuals, rather than reflect the abuse potential of deliriant drugs per se. Delirium-like hallucinogenic effects of tropane alkaloids is another key biomedical concern. For example, tropane alkaloids, especially scopolamine from Brugmansia arborea, have been used for centuries by Peruvian sorcerers to interact with spiritual forces147. Delirium-inducing properties of Solanaceae plants have also been used for banquets and entertainment, when intoxicated people felt and behaved ‘like animals’139. In the first half of 20th century, scopolamine was suggested to evoke “twilight sleep”, during which exposed individual honestly answered the questions without remembering it after recovering from the drug. While this led to several cases of interrogating criminals by police using scopolamine as a ‘truth serum’, this practice was deemed highly controversial and is discontinued, according to CIA report7. Nevertheless, toxic, amnestic and sedative effects of scopolamine have been adopted by Columbian criminals to render and kidnap their victims7, 148, thus becoming a societal problem in South America in recent years. ACS Paragon Plus Environment

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Another aspect to consider is the effects of anti-M deliriants on sexual behavior, since they have historically been used to stimulate fertility (Genesis 30:14-22) and sexual desires52. Representing naturally occurring aphrodisiacs, tropane alkaloids often stimulate libido but also cause toxicity in their users149, 150. Presently, both atropine and scopolamine are included in some, but not all, studies of drugs facilitating sexual assault (DFSA)151. Scopolamine may draw more attention in this regard due to a stronger sedation (than atropine) and overt amnestic effects151, which can promote sexual assault or violence152, 153. Some cases of hypersexuality are described following intake of other drugs, such as clomipramine, with overt anticholinergic side-effects154. Rodent literature supports the role of deliriants in the regulation of sexual behavior. For example, central microinjections of scopolamine in male hamsters increases intromission frequency and ejaculation latency, also causes continuous strings without the usual separation by dismounts155. Rodent and primate data also support sex differences in responses to scopolamine, since it inhibits sexual behaviors in females, but not in males156-158. However, such sexual inhibition following scopolamine may also be due to sedation, commonly observed in rodents159 and therefore meriting further scrutiny. A typical delirium experience usually involves confusion with hallucinations and complex visual imagery160. Neuropsychiatric effects of anticholinergic deliriants are dose-dependent, and include various positive and negative symptoms (Fig. 5), ranging from hallucinations to drowsiness, sedation, ataxia, amnesia, paranoia, picking behaviors and coma161,

162.

Psychotogenic effects of

deliriants is another problem, especially among abusers of anti-M drugs163 (also see similar animal data164). In addition to atropine-165, 166 and scopolamine-evoked psychoses167-169, self-injury and death during hallucinations170,

171

also occur, making deliriants a common cause of death due to self-

damage or toxicity171. For instance, only in the US, over 100000 cases of plant poisoning are reported annually, with a 16-% risk of death for some species172, further supporting clinical and societal importance of deliriant drugs. 6. Concluding remarks In summary, anticholinergic deliriant hallucinogens are an important class of drugs relevant to multiple CNS conditions in both humans and animal models (Tables 1 and 3). Some new CNS properties of tropane alkaloids include rapid (3-4 days) antidepressant properties of scopolamine173ACS Paragon Plus Environment

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ACS Chemical Neuroscience 175,

particularly important since depression is often resistant to traditional antidepressants176,

177.

However, scopolamine can also be pro-depressant in some models: for instance, in a rat model of Alzheimer’s disease, as it increases immobility time in the forced swim ‘despair’ test178,

179.

Furthermore, other drugs from this group may not show antidepressant activity, as, for example, atropine coma therapy (previously used in psychiatric practice) is not recommended for depressed patients180. Thus, further studies are needed to understand rapid antidepressant action of scopolamine and the role of anti-M effects in such responses. A core feature of anti-M drugs is their ability to induce delirium – an important mental state clinically overlapping with schizophrenia, unipolar and bipolar depression, anxiety and addiction181 (Fig. 5), with hyper- and hypoactivity182, 183 that quickly and unpredictably switch184. While similar alternating states can be observed in animal models after biperiden exposure185, the exact nature of this switch remains unclear. Likewise, while delirium can be triggered by many agents beyond tropane alkaloids, it is unclear how deliriant effects of the later are neurobiologically related to antiM delirium186, 187. As clinical delirium is a highly heterogenic condition188 (Fig. 4), the potential of deliriant drugs to evoke such heterogenic multifactorial state may indeed be promising. Recent findings implicate the immune system and microglia in the regulation of brain functioning and behavior, including psychiatric disorders189,

190.

Since delirium is associated with excessive

production of inflammatory mediators by microglia191, it may be interesting to examine the impact of deliriant hallucinogens on neuroimmune mechanisms and microglia activity following their acute and chronic administration. Moreover, since deliriant agents discussed here have several medicinal properties, including overt anti-Parkinson effects (Table 1), their clinical applications merit further scrutiny, and may eventually be expanded to target a wider range of CNS conditions. Overall, despite being used for millennia as psychoactive compounds, anticholinergic deliriants remain an interesting but under-studied group potently affecting multiple behavioral domains (e.g., cognition, sleep, memory, hallucinations, motor activity, anxiety and reward) relevant to many psychiatric conditions (Table 1). The study of deliriants can also improve our understanding of delirium per se (Fig. 2). While such cross-endophenotypic anticholinergics effects and the heterogeneity of delirium may complicate these studies, they may be beneficial in a long-run due to ACS Paragon Plus Environment

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unique potential to unravel connections between these endpoints, and the role of specific (anti-M) mechanisms in their modulation (Table 3). Collectively, this necessitates further studies of deliriant, cognitive, abuse-related and affective activity of anticholinergic hallucinogenic compounds.

Funding source: The research was supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851 to А.V.K. K.A.D. is supported by RFBR grant 18-34-00996 and Special Rector’s Fellowship for SPSU PhD Students.

Acknowledgement: The authors thank Lyudmyla E. Kalueva for providing an artwork for the TOC Graphic of this paper.

Conflict of interest: Authors declare no conflicts of interest.

Author Contributions: All authors have extensively contributed to this manuscript. A.V.K. conceived and coordinated the project, with conceptual input from V.A.Sh. All authors have participated in data collection, analysis and interpretation. A.M.L., K.A.D, T.O.K., S.L.Kh., K.N.Z. and V.A.Sh drafted the manuscript. A.M.L., K.A.D., A.V.K. and V.A.Sh. participated in critical review and further revision of the manuscript. All authors contributed to critical discussions and finalizing the manuscript before submission, and have approved its final form.


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Figure 1. Chemical structure of major tropane alkaloids (top row) and some synthetic analogs (bottom row) of tropane alkaloids. Inset - representation of various anticholinergic deliriant hallucinogens in scientific literature, based on Pubmed (www.ncbi.nlm.nih.gov/pubmed/) queries. Line diagram (top) shows the yearly cumulative numbers of papers published in 1955-2018 and mentioning the respective drugs in case reports, clinical studies, clinical trials (I-IV), evaluation studies, meta-analyses, observational studies and randomized controlled trials (the Y-axis is logarithmic, for better visuality). Bottom panel (pie-charts) presents relative number of articles published on various deliriant drugs (expressed in % of total) filtered for human studies (left) and animal studies (right), respectively.


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N N O

N OH

O

OH

OH N

OH N

N Benztropine

Biperiden

Tropicamide

Trihexyphenidyl

Procyclidine

Number of articles in Pubmed

% of total (clinical)

% of total (pre-clinical)


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Figure 2. Biosynthetic pathway of major tropane alkaloids


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Figure 3. Chemical synthesis of atropine (inset)


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Figure 4. Biological effects of anti-muscarinic hallucinogenic deliriants. The most known deliriants, atropine and scopolamine, are extracted from Atropa belladonna, used for ages for various purposes. In ancient times, it has been used as an efficient poison, and for witchcraft in medieval times. In the renaissance era, they became popular among women for expanding pupils. In the 20th century, atropine and scopolamine were actively used for research and also were introduced into clinical practice, to treat vomiting and nausea. Currently, their putative ‘fast’ antidepressant properties are also being studied.

Poison used by assassins and military structures

Treatment for postoperative nausea and vomiting

Atropa belladonna (AB)

Extract of AB has been widely used among renaissance era to extend eye-pupils (wide pupilsbeauty standard for women of this era)

Nowadays anti-cholinergic deliriants are considered as a potential treatment for depression (e.g. scopolamine can modulate activity of serotoninergic system


21


Figure 5. Summary of clinical delirium-like states common for clinical delirium or evoked by antimuscarinic deliriant hallucinogens. Note that hyper- and hypoactive states often fluctuate and switch. Most of the states shown in this diagram are easy to model in animal experimental models, and are commonly seen in clinical patients following intake of anticholinergic deliriants (see Table 1 for details).

Hyperactivity

Hypoactivity

Confusion, disturbed attention Hallucinations Hyperlocomotion Agitation Illusions and delusions Restlessness Nervousness/Anxiety Hypersexuality Sleep problems Aggression

Hypolocomotion Reduced alertness Drowsiness Lethargy Disordered thought Executive dysfunction

Mixed type

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Cognitive deficits


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Table 1. Summary of clinical effects of antimuscarinic deliriants (also see Table 2) Drug

Therapeutic effects

Side effects

Atropine

Reduced motion sickness, ophthalmic effect

Delirium-related: Confusion, hallucinations, excitement, disorientation Cognitive: Memory impairment Other behavioral: Anxiety, coma and convulsions Body-related: Blurred vision, change in color vision, difficulty seeing at night, eye pain or stinging, fast or irregular heartbeat or pulse, high photosensitivity, hyperthermia

Scopolamine

Reduced motion sickness

Delirium-related: Confusion, hallucinations, mood or mental changes, restlessness Cognitive: Impairment of selection/evaluation of environmental information and memory Other behavioral: Dizziness, faintness, tiredness, anxiety/fear Body-related: Blurred vision, chest pain/discomfort, difficulty urinating, dilation of pupils, lightheadedness when getting up, eye pain, skin redness, muscle weakness, nausea or vomiting, rash, shortness of breath slow or irregular heartbeat, sweating, unusually warm skin

Hyoscyamine

Mydriatic, cardiovascular, antispasmodic effects

Delirium-related: Confusion, hallucinations, disorientation, depersonalization Cognitive: Memory impairment Other behavioral: Auditory changes, ataxia Body-related: Muscular incoordination, blurred vision, hyperthermia, reduced salivation

Benztropine

Anti-Parkinson effects

Delirium-related: Altered consciousness, false fact-less beliefs, unusual excitement, nervousness or restlessness Cognitive: Memory impairment Other behavioral: Dizziness, faintness, tiredness, loss of consciousness, shakiness and unsteady walk, motor incoordination Body-related: Poor/blurred vision, cold skin, lightheadedness, muscle weakness, nausea or vomiting, breathing problems, nosebleeds, numbness or tingling in the face, arms or legs, sweating, tearing, wheezing

Biperiden


Delirium-related: Anxiety, confusion (about identity, place and time), false or unusual sense of well-being, irritability, nervousness, restlessness, trouble sleeping, unusual tiredness Cognitive: Visual memory impairment, short-term memory impairment Other behavioral: Disturbed behavior, dizziness, faintness, twisting, uncontrolled movement of the face, hands, arms or legs, shaking Body-related: Chest pain, chills, cold sweats, reduced or painful urination, lightheadedness, dry mouth, hyperventilation, slow or irregular heartbeats, shortness of breath

Tropicamide

Ophthalmic effect

Delirium-related: Confusion, hallucinations Cognitive: Memory impairment Other behavioral: Clumsiness or unsteadiness, slurred speech, drowsiness, tiredness and general weakness, unusual/atypical behaviors, especially in children Body-related: Fast heartbeat, flushing or redness of face, increased thirst, dry mouth, skin rash, swollen stomach

Trihexypheni dyl


Delirium-related: Nervousness, disorientation (especially in children) Cognitive: Memory impairment Other behavioral: Delusions of persecution, mistrust, suspiciousness and combativeness Body-related: Dizziness, mild nausea

Procyclidine


Delirium-related: Agitation, confusion, overactive behavior, sexual hyperactivity, irritability Cognitive: Memory impairment Body-related: Dry mouth, blurred vision, nausea, vomiting, epigastric distress, constipation, lightheadedness, muscular weakness


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Table 2. Chemical, market and street names of common anticholinergic deliriants (see Table 1 for summary of clinical effects) Drugs

Selected marketed names

Atropine*,**

Atropine Care, Isopto Atropine

Scopolamine (hyoscine, scopine tropate)**

Scopace, Maldemar

Hyoscyamine (daturine)*,**

Anaspaz, Cystospaz, Hyosyne, Levbid, Levsin, Levsinex, NuLev, Symax, Oscimine

Benztropine***

Cogentin, Cogentinol, Cogentine, Akitan, Bensylate, Cobrentin

Biperiden****

Akineton HCl, Akinophyl, Akineton, Dekinet, Ipsatol, Paraden, Tasmolin

Tropicamide (benzeneacetamide)

Mydryacyl, Mydriaticum, Mydrin, Mydrum, Tropimil, Tryptar, Visumidriatic

Trihexyphenidyl****

Atrane, Pipanol, Tremin, Antitrem, Anti-Spas, Aparkan, Broflex, Aparkane, Novohexidyl, Paralest, Pargitan, Parkinane, Parkopan, Partane, Peragit, Pyramistin, Rodenal, Sedrena, Trihexane, Trihexy, Triphedinon

Procyclidine****

Kemadrin, Kemadrine, Arpicolin, Kemadren, Osnervan, Procyclid

*Commonly used as a sulfate salt **These drugs share the street names, originating from Datura stramonium: Jamestown weed, Jimson weed, datura, stinkweed, devil’s snare, devil’s seed, angel/devil’s trumpet, Korean morning glory, crazy tea, moonflower, thorn apple, malpitte, ***Commonly used as a mesylate salt ****Commonly used as a hydrochloride salt


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Table 3. A brief summary of muscarinic acetylcholine receptor subtypes (M1-M5) and deliriant binding profiles in mammals (+ potent activity, 0 no effects, ? unclear effects or no data) Drugs

M1

M2

M3

M4

M5

References

Atropine

+++

++

++

+

+

192, 193

Scopolamine

+++

+++

+++

+++

+

194

Hyoscyamine

0

+++

0

0

0

195

Benztropine

+

0

+

0

0

196

Biperiden

+++

+

+++

+++

+++

197, 198

Tropicamide

+++

0

0

+++

0

199, 200

Trihexyphenidyl

+++

+

+

+++

+

201

Procyclidine

+++

+++

?

+++

?

202


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Table 4. A brief summary of symptoms recognized as anticholinergic syndrome (AS) commonly evoked by anticholinergic deliriant hallucinogens (also see Table 1 for details of drug-evoked mental effects)

AS symptoms

Drugs most commonly evoking the symptoms

Tachycardia

Atropine, scopolamine203

High blood pressure


Fever


Agitation, anxiety

Atropine, scopolamine203, tropicamine204

Memory impairment


Sweating

Atropine, scopolamine203, tropicamine204

Palpitations

Tropicamide204

Blurred vision, mydriasis

Atropine, scopolamine203, tropicamine204, biperiden205

Dry mouth

Atropine, scopolamine203, tropicamine204, biperiden205

Abdominal discomfort

Biperiden205


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Table 5. A brief summary of preclinical effects of tropane anti-cholinergic tropane alkaloids (see 74 for review and Tables 1 and 6 for a summary of similar clinical effects) Drug

Effects in rodents

Atropine

Delirium-like: Impaired stimulus sensitivity, sensory discrimination, vision and behavioral patterning Cognitive: Reduced passive avoidance, impaired memory Other: Evoked sleep-like slow wave cortical activity

Scopolamine

Delirium-like: Increased spontaneous locomotion, longer latency between stimuli in the choice reaction task Cognitive: Impaired working and social memory, fear conditioning Other: Lower food motivation, antidepressant-like effects

Hyoscyamine

Delirium-like: Atropine-like stimulatory effects on central and motor neurons Other: Nociceptive effect

Benztropine

Delirium-like: Increased locomotion and rearing Cognitive: Cognitive deficits

Biperiden

Delirium-like: Alternating hyper- and hypoactive states Cognitive: Memory impairments (passive avoidance test) Other: Antidepressant-like effects

Tropicamide

Delirium-like: Increased anxiety-like behavior in rats Cognitive: Cognitive deficits Other: Suppressed stereotypic jaw movements in a model of Parkinson’s disease

Trihexyphenidyl

Delirium-like: Sleep deficits, enhanced cocaine effects, hyperactivity and increased male sexual behavior Cognitive: Cognitive deficits

Procyclidine

Delirium-like: Agitation, confusion Cognitive: Cognitive deficits


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Table 6. Selected personal experiences with various deliriant hallucinogens described in the Erowid database (www.erowid.org, accessed November 2018) and/or published case reports. Note a strikingly overlapping clinical picture of drug-evoked delirium and hallucinogenic states. Drugs Atropine

Dose 32 mg i.v. 2 eye-drops

Scopola-mine

1.6 mg i.v. 7 mg orally

Patch 6 mg orally

Hyoscyamine

Benztropine

Biperiden

3 mg orally 7 mg orally 250 mg sublingually 2 mg i.m. 2 mg orally 4 mg orally 50 mg orally 4 mg orally 6 mg orally

Tropicamide

Not specified, i.v.

Trihexyphenidyl

Not specified, orally

Procyclidine

300 mg orally 15 mg orally 8 tablets

Neurobehavioral effects Disorientation, delayed recall, inattention, delusions of persecution, following only simple commands, inability to cooperate during a formal mental examination Psychomotor excitation, disorientation to time and place, delusions and visual hallucinations (seeing mice) Visual hallucinations for 11 days, severely impaired vision for 3 days Blurred vision, ataxia and slurred speech after 30 min, overt delirium, low muscle tone after 1 h, severe myorelaxation, impaired hearing, colorful bright visual hallucinations, poor vision, impaired depth perception (walls ‘breathing’, objects swirling and taking on living forms), robust frightening hallucinations, total disorientation after 2 h. Confusion, poor concentration and memory, blurry vision, dilated pupils, mild paranoia after 16 h. General perception: highly negative Sleep-like walking in a dreamy state within several hours Perceptual changes, blurred vision, poor concentration, severe spatial distortion, incoordination after 40 min; muscle weakness, lucid dreaming sleep, poor perception, visual and auditory hallucinations, communication with imaginary persons, talking to himself, memory loss, fatigue, sleepiness after 2-4 h, poorer concentration 24 h later. General perception: negative Confusion, hallucinations, memory loss, Delirium Impaired perception (moving furniture, volumetric vision of flat picture) Feeling of rush after injection Delirium, hallucinations, restlessness, disorientation Confusion, agitation, aimless wandering Feeling of relaxation and increased sociability, somnolence and disorientation to time/place, incoherent speech, blurry vision, resting tremor, poor appetite, hypotonia, flaccidity in the facial muscles and slow gait Improved mood, reduced agitation and anxiety, normalized sleep-wake schedule Auditory hallucinations and bizarre behaviors (talking to himself, picking up imaginary objects), altered mental status, disorientation, restlessness, insomnia Feeling of fun, joy, but also horrific, scary and dangerous experience Dissociation, hallucinations, anxiety and blurred vision Powerful relief and relaxation (in combination with heroin), but hallucinations and dissociation after tropicamide alone Euphoria (feeling of ‘loving everybody in the world’) and increased sociability Animated and pleasant hallucinations Auditory and visual hallucinations (imaginary objects around) Agitation and hallucinations Disorientation to time/place, agitation, emotional lability and frequent fears Delirium, disorientation and motor incoordination


References or Erowid record ID 206 207 208

16448

36749 27661

58661 39749 21232 209 210 211 212

213 214 215 101 101 209 209 100 216 217 218

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References 1. Georgiev, V., Marchev, A., Berkov, S., and Pavlov, A. (2013) Plant In Vitro Systems as Sources of Tropane Alkaloids. In Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes (Ramawat, K. G., and Mérillon, J.-M., Eds.), pp 173-211, Springer Berlin Heidelberg, Berlin, Heidelberg. 2. Philipov, S., and Doncheva, T. (2013) Alkaloids Derived from Ornithine: Tropane Alkaloids. In Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes (Ramawat, K. G., and Mérillon, J.-M., Eds.), pp 343-358, Springer Berlin Heidelberg, Berlin, Heidelberg. 3. Schulte, M. L., and Lindsley, C. W. (2012) Tropane-Based Alkaloids as Muscarinic Antagonists for the Treatment of Asthma, Obstructive Pulmonary Disease, and Motion Sickness, Bioactive Heterocyclic Compound Classes: Pharmaceuticals, 21-36. 4. Gualtieri, F., Conti, G., Dei, S., Giovannoni, M. P., Nannucci, F., Romanelli, M. N., Scapecchi, S., Teodori, E., Fanfani, L., and Ghelardini, C. (1994) Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters, Journal of medicinal chemistry 37, 1704-1711. 5. Oksman-Caldentey, K., and Arroo, R. (2000) Regulation of tropane alkaloid metabolism in plants and plant cell cultures. In Metabolic engineering of plant secondary metabolism pp 253-281, Springer. 6. Grynkiewicz, G., and Gadzikowska, M. (2008) -Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs, Pharmacological Reports 60, 439. 7. Ullrich, S. F., Hagels, H., and Kayser, O. (2017) Scopolamine: a journey from the field to clinics, Phytochem Rev 16, 333-353. 8. Mein, K. (1833) Ueber die Darstellung des Atropins in weißen Krystallen, Ann. Pharm 6, 67-72. 9. Smulyan, H. (2018) The Beat Goes On: The Story of 5 Ageless Cardiac Drugs, Am J Med Sci. 10. Cieri, U. R. (2005) Identification and estimation of the levo isomer in raw materials and finished products containing atropine and/or hyoscyamine, J AOAC Int 88, 1-4. 11. Griffin, W. J., and Lin, G. D. (2000) Chemotaxonomy and geographical distribution of tropane alkaloids, Phytochemistry 53, 623-637. 12. He, Y., Luo, J., and Kong, L. (2011) Preparative separation of atropine and scopolamine from Daturae metelis Flos using pH-zone-refining counter-current chromatography with counter-rotation and dual-mode elution procedure, Journal of separation science 34, 806-811. 13. Cardillo, A. B., Perassolo, M., Sartuqui, M., Talou, J. R., and Giulietti, A. M. (2017) Production of tropane alkaloids by biotransformation using recombinant Escherichia coli whole cells, Biochemical Engineering Journal 125, 180-189. 14. Wang, J., Li, J.-l., Li, J., Li, J.-x., Liu, S.-j., Huang, L.-q., and Gao, W.-y. (2017) Production of Active Compounds in Medicinal Plants: From Plant Tissue Culture to Biosynthesis, Chinese Herbal Medicines 9, 115125. 15. Xia, K., Liu, X., Zhang, Q., Qiang, W., Guo, J., Lan, X., Chen, M., and Liao, Z. (2016) Promoting scopolamine biosynthesis in transgenic Atropa belladonna plants with pmt and h6h overexpression under field conditions, Plant Physiology and Biochemistry 106, 46-53. 16. Cordell, G. A. (2013) Fifty years of alkaloid biosynthesis in Phytochemistry, Phytochemistry 91, 29-51. 17. Philipov, S., and Doncheva, T. (2013) Alkaloids derived from ornithine: tropane alkaloids. In Natural Products pp 343-358, Springer. 18. Talapatra, S. K., and Talapatra, B. (2015) Chemistry of plant natural products, Springer. 19. Kraut, K. (1863) Ueber das Atropin, Justus Liebigs Annalen der Chemie 128, 280-285. 20. Willstätter, R. (1901) Synthesen in der Tropingruppe. I. Synthese des Tropilidens, Justus Liebigs Annalen der Chemie 317, 204-265. 21. Robinson, R. (1917) LXIII.—A synthesis of tropinone, Journal of the Chemical Society, Transactions 111, 762-768. 22. Iida, H., Watanabe, Y., and Kibayashi, C. (1985) A new synthetic route to tropane alkaloids based on [4+ 2] nitroso cycloaddition to 1, 3-cycloheptadienes, The Journal of Organic Chemistry 50, 1818-1825. 23. Nocquet, P. A., and Opatz, T. (2016) Total Synthesis of (±)-Scopolamine: Challenges of the Tropane Ring, European Journal of Organic Chemistry 2016, 1156-1164. 24. Pollini, G. P., Benetti, S., De Risi, C., and Zanirato, V. (2006) Synthetic approaches to enantiomerically pure 8-azabicyclo [3.2. 1] octane derivatives, Chemical reviews 106, 2434-2454. 25. Bédard, A.-C., Longstreet, A. R., Britton, J., Wang, Y., Moriguchi, H., Hicklin, R. W., Green, W. H., and Jamison, T. F. (2017) Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine, Bioorganic & medicinal chemistry 25, 6233-6241. ACS Paragon Plus Environment

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DARK classics in chemical neuroscience: atropine, scopolamine and

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