AMINES AND NEUROTRANSMITTERS

1. AMINES ANDNEUROTRANSMITTERS

2. AMMONIUM SALTS • Ammonium salts can be re-converted to amines by treatment with base. • Base removes a proton from the nitrogen atom of the amine, regenerating the neutral amine.

3. PROBLEM • What product is formed when each ammonium salt is treated with NaOH?

4. AMMONIUM SALTS AS USEFUL DRUGS • Many amines with useful medicinal properties are sold as their ammonium salts. • Since the ammonium salts are more water soluble than the parent amine, they are easily transported through the body in the aqueous medium of the blood.

5. Dopamine • Dopamine affects brain processes that control movement, emotions, and pleasure. • When dopamine-producing neurons die and there is too little dopamine in the brain, an individual loses control of fine motor skills and Parkinson’s disease results. • the level of dopamine in the brain cannot be increased simply by giving an individual dopamine, because dopamine does not cross the blood–brain barrier. L-Dopa, a precursor of dopamine, can travel from the bloodstream to the brain, so it is an effective treatment for Parkinson’s disease. Elevated dopamine levels are also unhealthy and are associated with schizophrenia. • Dopamine plays an important role in addiction. Normal dopamine levels give an individual a pleasurable, satisfied feeling. Increased levels result in an intense “high.” Drugs such as heroin, cocaine, and alcohol increase dopamine levels. When dopamine receptors are stimulated more than normal, the number and sensitivity of the receptors decreases, and an individual requires more of a drug to feel the same sense of pleasure.

6. SEROTONIN • The neurotransmitter serotonin is synthesized from the amino acid tryptophan. • Serotonin plays an important role in mood, sleep, perception, and temperature regulation.

7. SEROTONIN • A deficiency of serotonin causes depression. • Understanding the central role of serotonin in determining one’s mood has led to the development of a wide variety of drugs for the treatment of depression. • The most widely used antidepressants today are selective serotonin reuptake inhibitors (SSRIs).

8. selective serotonin reuptake inhibitors (SSRIs) • These drugs act by inhibiting the reuptake of serotonin by the presynapticneuron, thus effectively increasing its concentration. • Fluoxetine (trade name: Prozac) and sertraline (trade name: Zoloft) are two common antidepressants that act in this way.

9. The discovery that migraine headaches result from improper levels of serotonin in the brain has led to the synthesis of several drugs that combat the pain, nausea, and light sensitivity that are associated with this condition. • These drugs include sumatriptan (trade name: Imitrex) and rizatriptan (trade name: Maxalt).

10. Drugs that interfere with the metabolism of serotonin have a profound effect on mental state. • For example, bufotenin, isolated from Bufo toads from the Amazon jungle, and psilocin isolated from Psilocybe mushrooms, are very similar in structure to serotonin and both cause intense hallucinations How are serotonin, bufotenin, and psilocin similar in structure? Classify the amines in these three compounds as 1°, 2°, or 3°.

11. ACETYLCHOLINE AND NICOTINE ADDICTION • Acetylcholine is a quaternary ammonium ion that serves as a neurotransmitter between neurons and muscle cells. • In the brain, acetylcholine is involved in memory, mood, and other functions.

12. ACETYLCHOLINE AND NICOTINE ADDICTION • The pleasurable high that a smoker feels is due to nicotine interacting with acetylcholine receptors. • At low concentrations, nicotine is a stimulant because it binds to these receptors, resulting in a feeling of well-being and alertness. • Other nerve cells are also activated and this releases dopamine. The sense of pleasure resulting from the release of dopamine is what causes nicotine to be addictive. • Over time receptors are inactivated and some degenerate, so tolerance to nicotine develops and larger quantities are needed to maintain the same sense of pleasure.

13. EPINEPHRINE AND RELATED COMPOUNDS • While neurotransmitters are the chemical messengers of the nervous system, hormones are the chemical messengers of the endocrine system. • A hormone is a compound produced by an endocrine gland, which then travels through the bloodstream to a target tissue or organ. • Epinephrine, or adrenaline as it is commonly called, is a hormone synthesized in the adrenal glands from norepinephrine (noradrenaline).

14. EPINEPHRINE AND RELATED COMPOUNDS • When an individual senses danger or is confronted by stress, the hypothalamus region of the brain signals the adrenal glands to synthesize and release epinephrine, which enters the bloodstream and then stimulates a response in many organs. • Stored carbohydrates are metabolized in the liver to form glucose, which is further metabolized to provide an energy boost. Heart rate and blood pressure increase, and lung passages are dilated. • These physiological changes are commonly referred to as a “rush of adrenaline,” and they prepare an individual for “fight or flight.”

15. DERIVATIVES OF 2-PHENYLETHYLAMINE • Like epinephrine and norepinephrine, a large number of physiologically active compounds are derived from 2-phenylethylamine, C6H5CH2CH2NH2. • Each of these compounds has a common structural unit: a benzene ring bonded to a two-carbon chain that is bonded to a nitrogen atom.

16. amphetamine and methamphetamine • amphetamine and methamphetamine are derivatives of 2-phenylethylamine that are powerful stimulants of the central nervous system. • Both amines increase heart rate and respiratory rate. Since they increase glucose concentration in the bloodstream, they decrease hunger and fatigue. • While amphetamine and methamphetamine may be prescribed for attention deficit hyperactivity disorder (ADHD) and weight reduction under the trade names Adderall and Desoxyn, respectively, they are highly addictive and widely abused drugs that must be used with extreme care. • Both amphetamine and methamphetamine increase the level of dopamine in the brain, causing a pleasurable “high.”

17. Pseudoephedrine • Pseudoephedrine, the decongestant in Sudafed, is another derivative of 2-phenylethylamine. • Since pseudoephedrine can be readily converted to methamphetamine, it has been replaced in many products by a related amine, phenylephrine. • For example, Pfizer markets its pseudoephedrine free decongestant as Sudafed PE. • Products that contain pseudoephedrine are still over-the-counter remedies, but they are now stocked behind the pharmacy counter so their sale can be more closely monitored.

18. PROBLEM

19. DRUGS TO TREAT ASTHMA • The search for drugs that were structurally related to epinephrine but exhibited only some components of its wide range of biological activities led to the discovery of some useful medications. • Both albuterol and salmeterol are derivatives of 2-phenylethylamine that dilate lung passages; that is, they are bronchodilators. They do not, however, stimulate the heart. • This makes both compounds useful for the treatment of asthma. • Albuterol is a short-acting drug used to relieve the wheezing associated with asthma. • Salmeterol is much longer acting, and thus it is often used before bedtime to keep an individual symptom free overnight.

20. PROBLEM • Classify the amines and the alcohols (not the phenols) in albuterol and salmeterol as 1°, 2°, or 3°.

21. HISTAMINE AND ANTIHISTAMINES • Histamine is a neurotransmitter that binds to two different receptors, the H1 and H2 receptors, and produces a wide range of physiological effects on the body. • Histamine is a vasodilator (it dilates capillaries), so it is released at the site of an injury or infection to increase blood flow. • It is also responsible for the symptoms of allergies, including a runny nose and watery eyes. In the stomach, histamine stimulates the secretion of acid.

22. HISTAMINE AND ANTIHISTAMINES • Antihistamines bind to the H1 histamine receptor, but they evoke a different response. • An antihistamine like chlorpheniramine or diphenhydramine, for example, inhibits vasodilation, so it is used to treat the symptoms of the common cold and environmental allergies. • These antihistamines also cause drowsiness by crossing the blood–brain barrier and binding to H1 receptors in the central nervous system. • Newer antihistamines like fexofenadine (trade name: Allegra) also bind to H1 receptors, but they do not cause drowsiness because they cannot cross the blood–brain barrier and bind to the H1 receptors in the central nervous system.

24. Drugs that bind to the H2 receptor produce a different effect. • For example, cimetidine (trade name: Tagamet) binds to the H2 histamine receptor and, as a result, reduces acid secretion in the stomach. • Thus, cimetidine is an effective anti-ulcer medication.