1. Tropane Alkaloids Tropane ring system Class of alkaloids that contain a tropane ring system in their chemical structure. Naturally produced in plants of the family Solanaceae. Tropane alkaloids biologically perform one of two functions: 1.Anticholinergics (blocks the activity of acetylcholine) 2.Stimulants

2. Examples of Tropane Alkaloids AtropineCocaine Tropane Ring Nightshade bush with “Devils Berries” Coco bush Tropanone

3. Biosynthesis Plant evolutionary map for producing tropane alkaloids

4. Nightshade and It’s Berries The nightshade plants latin name is Atropa belladonna, Atropa is the goddess of fate and the one who ends lives and belladonna means beautiful women. The berries of the Nightshade bush are sweat tasting but are quite deadly and were often used as a poison in the Roman Empire to kill off enemies. For example, it is known that Augustus and Claudius wives both used these berries to kill off contemporaries. The berry before the Middle Ages was used as an anesthetic to carry out surgery. Small doses of the berry juice will slow down the heart rate while causing delirium and hallucinations, higher doses will kill. Middle age eye operation Emperor Claudius Emperor Caesar Augustus Nightshade leaves and berry

5. Tropinone – A component of Nightshade Richard Willstätter Robert Robinson Scheele (top) and Serturner (bottom) Tropinone can actively be extracted from nightshade berries and jimson weed and serves as the precursor to all tropane alkoloids (much like cholesterol is to animal steroids). First isolated by Scheele and Serturner (among other tropane alkoloids in the 1800’s) and served as a synthetic challenge. In 1901, Willstätter (a Jewish-German Nobel-Laureate chemist who fled to Switzerland in WWII) first synthesized tropinone with an exhaustive synthesis. Robinson later (1917) synthesized it in a single step as demands for atropine, a chemical warfare agent, required tropinone in its synthesis.

6. Willstätter Synthesis (1901) 15 steps, 0.75% overall yield using very expensive reagents! Richard Willstätter

7. Robinson’s Synthesis (1917) Robert Robinson Original Plan: Use a double Mannich reaction to make in 1 step. This worked, but the yield was very low (ie 17%)! Modified Synthesis: Use acetone- dicarboxylate instead. The two carboxylic acids can later be removed. Requires two steps but a higher yield is obtained (up to 90% through this route)…. Brilliant!!!

8. Atropine – Also found in Nightshade Berries Acetyl choline Atropine is one of the active poisons found in the deadly nightshade berries. It is also found in Jimsomweed, mandrake and other plants in the Solanaceae family. It functions by inhibiting the M 2 muscarinic acetylcholine receptor, where they function to prevent the slowing of heart rate (but does not inhibit nicotinic receptors until higher doses). At higher doses will cause muscles associated with the parasympathetic nerve system to relax (or become paralyzed). Target of Apropine Effected Synapses Atropine

9. Uses as a Drug Used as a cycloplegic (paralyzes the ciliary muscles of the eye) leading to dilation of the pupils. This allows optometrist to get a good look into the eye. Injections of atropine are used for bradycardia (an extremely low heart rate), asystole and pulseless electrical activity (PEA) in cardiac arrest. This works because the main action of the vagus nerve of the parasympathetic system on the heart is to decrease heart rate. Atropine is also used as a treatment against organophosphates (Tabun, Sarin, Soman, and VX) used in chemical warefare. Troops will actually carry autoinjectors containing atropine. These gases destroy acetylcholinesterases which deactivate the activity of acetylcholine on nerves.

10. Cocaine Obtained from the leaves of the Coco plant. Is currently one of the most popular and most addictive drugs in the U.S. The cocaine market exceeded 70 billion dollars in 2005, exceeding revenues of corporations such as Starbucks. There is a huge demand for cocaine in the U.S. particularly among individuals who are making large enough incomes to afford luxurious spending.

11. History of Cocaine For thousands of years, indigenous peoples from South America have chewed the leaves of Coco plants. Their mummies were buried with it and their pottery depicted images of people chewing it. When the Spanish arrived in South America, they quickly noticed the natives chewing the leaves along with tobacco. One account of Nicolas Monardes describe their practice as the following: “When they wished to make themselves drunk and out of judgment they chewed a mixture of tobacco and coca leaves which make them go as they were out of their wittes.” The Coco leaf was eventually extracted in 1855 for cocaine by the German Scientist Friedrich Gaedcke and several other scientist is years to come improved on the process.

12. History (Cont.) Coco leaves were then used in the last 1800’s as an addition to beverages including Coca-Cola and Mariani wine (which Pope Leo XIII awarded the Vatican gold metal to for its claim to restore health, strength, energy and vitality). Ironic by today’s standards, cocaine was used to treat morphine addition. In 1885 the U.S. manufacturer Parke-Davis sold cocaine in various forms, including cigarettes, powder, and even a cocaine mixture that could be injected directly into the user's veins with the included needle. The company promised that its cocaine products would "supply the place of food, make the coward brave and render the sufferer insensitive to pain.” The addictive properties of cocaine had become clear, and perceived problems with cocaine use began to capture public attention in the United States by the turn of the 20 th century, however, it wasn’t until 1970 that cocaine actually became a controlled substance.

13. Cocaine – Inhibits a Dopamine Uptake Transporter Cocaine works in the synaptic cleft of neuron cells by preventing uptake of dopamine (which eventually degrades dopamine and stops a neurotransmission signal). With Cocaine in the system a dopamine response will last much longer then normally.

14. Effects of Cocaine Cocaine is a powerful nervous system stimulant. Its effects can last from 15–30 minutes to an hour, depending upon the method of ingestion. Cocaine increases alertness, feelings of well-being and euphoria, energy and motor activity. Athletic performance may be enhanced in sports where sustained attention and endurance is required. Anxiety, paranoia and restlessness are also frequent. With excessive dosage, tremors, convulsions and increased body temperature are observed. Conclusion: Don’t use cocaine!

15. Common Neurotransmitters GABAAcetylcholine Dopamine Norepinephrine Epinephrine Serotonin Melatonin Histamine Oxytocin