Central Nervous System Drugs: Anxiolytics, Sedative-Hypnotics, and More

1. Dr. Ahmed M. Alafeefy E-mail: a.alafeefy@sau.edu.sa Tel: 0507069896

2. My research group Hiking at Huolu Mountain

3. 1. Anxiolytics, sedative-hypnotics 2. Antiepileptics 3. Antipsychotics 4. Antidepressants 5. Analgesics 6. Central stimulants Medicinal Chemistry Chapter 2. Central Nervous System Drugs

4. The central nervous system (CNS) It represents the largest part of the nervous system, including the brain and the spinal cord. Together with the peripheral nervous system, it has a fundamental role in the control of behavior.

5. Central Nervous System cerebra pituitary cerebel pons medulla optocele 脑 Brain

6. Central Nervous System heel of nervi spinales cervical nerve spinal cord thoracic nerve anterior of nervi spinales nervi spinales nervi lumbales nervi sacrales nervi coccygeus Spinal cord 脊髓

7. 神经系统：外周神经系统 Central Nervous System olfactory nerve optic nerve pathetic nerve oculomotor nerve trifacial nerve abducent nerve facial nerve nervi statoacusticus nervi glossopharyngeus pneumogastric nerve nervi hypoglossus nervus accessorius 脑神经 nervi cerebrales

8. Central Nervous System rami cutaneus spinal ganflion heelpiece rami posterior nervi spinalis postcornu rami anterior anterior angle anterior root trunk of spinal nerve intercostal nerves sympathetic ganglia rami lateralis cutaneous rami cutaneus anterior 脊神经 nervi spinales

10. Chapter 2. 1. Anxiolytics, Sedative-hypnotics 镇静催眠药 What you need to know: 1. Name and structure of the drug 2. History of the drug 3. Chemical synthesis 4. Physical and chemical properties 5. Use and its metabolism 6. Other drugs of the same class 7. SAR

11. Anxiolytics: Drugs used for the treatment of symptoms of anxiety, including benzodiazepines. Sedatives: Drugs causes calmness, relaxation, reduction of anxiety. Sedatives may be referred to as tranquilizers, depressants, anxiolytics, soporifics, sleeping pills, downers, or sedative-hypnotics, including barbiturates, benzodiazepines, zolpidem. Hypnotics: Drugs that induce sleep, used in the treatment of severe insomnia, including barbiturates, benzodiazepines, zolpidem.

12. The Ligand-gated ion channelsare a group of transmembrane ion channels that are opened in response to binding of a chemical messenger. The ion channel is regulated by a neurotransmitter ligand and is usually very selective to one or more ions like Na+, K+, Ca2+, or Cl-. Many important ion channels are ligand-gated, including GABA, NMDA, acetylcholine, glycine receptors, and the 5-HT3 serotonin receptor, and they show a great degree of homology at the genetic level. Ligand-gated ion channels

13. GABA agonist: Benzodiazepines increase pore opening frequency---sleep pills and anxiety medications. Imidazopyridines and barbiturates increase pore opening duration---used as sedatives.

14. Based on chemical structures, this class of drugs can be divided into three groups: • Barbiturates • Benzodiazepines • 3. Others Barbiturate Benzodiazepines

15. In the early and middle of the last century, barbiturates are the main drugs used as sedative-hypnotics. For the next half of the last century, benzodiazepines are widely used because they are safer, and less likely to cause drug-dependence.

16. Barbiturates are drugs that act as central nervous system (CNS) depressants, and by virtue of this they produce a wide spectrum of effects, from mild sedation to anesthesia. Some are also used as anticonvulsants. Barbiturates are GABA (gamma-aminobutyric acid) agonists, acting on the GABAA receptor. GABA is the principal inhibitory neurotransmitter in the mammalian CNS. Barbiturates are derivatives of barbituric acid.

17. Barbiturates

18. Add Hydrogen

19. Properties of Amobarbital 1. Acidic. It dissolves in basic solutions Amobarbital is able to be dissolved in solutions of sodium hydroxide or sodium carbonate, only if pKa = 7.9

20. When it dissolves in sodium-containing basic solutions, it becomes sodium salt Amobarbital sodium is used as injections.

21. The sodium solution absorbs CO2 and the free drug precipitates from the solution, Suggestion: it cannot be exposed long in the air.

22. 3. The sodium solution absorbs water and decomposes Suggestion: it cannot be left long in the air.

23. When 10% sodium solution is placed at 35oC, 22% of the drug decomposes in one month. If it is stored at 1oC for two month, the drug is basically stable. Be caution if the injection is used In order to avoid the invalidation of the injections, be careful the following Avoid pre-formulation, sterilization by heating should be made in powder-injection, dissolved before used

24. It reacts with metal ions such as Cu2+, Hg2+, and Ag+, for example, it reacts with Cu2+ forming a purple color precipitate.

25. It reacts with silver nitrate forming a white precipitate.

26. Chemical synthesis of Amobarbital (from Diethyl malonate)

27. Metabolism of Amobarbital It metabolizes in the liver

28. Clinical use of Amobarbital As sedative-hypnotics, and Antiepileptics

29. R2: CH3 fast action If R (R1) = H, no activity; it needs to be 2-5 carbon chains or 1 phenyl group The sum of R and R1 needs to be 4-8 SAR of barbituates O: replace with S fast action

30. Long-term relief barbituates Phenobarbital Barbital

31. Mid-term relief barbituates amobarbital cyclobarbital

32. Short-term relief barbituates pentobarbital secobarbital

33. Super short-term relief barbituates hexobarbital thiopental sodium

34. The benzodiazepinesare used for short-term relief of severe, disabling anxiety or insomnia. Long-term use can be problematic due to the development of tolerance and dependency. They act on the GABA receptor GABAA as agonist. They began to be widely prescribed in the 1960s and 1970s.

35. Naming

37. Structural characteristics A phenyl fused with a 7-member imine lactam

38. Chlordiazepoxide is the first member of the benzodiazepines synthesized.

39. Diazepam (Valium) widely used for several anxiety states

40. Chemical synthesis

41. Properties of Diazepam • Hydrolysis • At 37 oC and acidic conditions, the imine bond is hydrolyzed. • At neutral pH or basic condition, it is rapidly cyclized. • Under the interaction of gastric acid, ring opens between site • 4 and 5 • When the compound gets into the basic atmosphere of small • intestinal, it is cyclized again. The ring opening does not affect • its bioavailablity.

42. SAR

43. The triazo moiety increases the drug’s binding affinity and stability. As a result, the potency is greatly increased. Alprazolam (佳乐定）

44. Benzodiazepines have replaced the barbiturates because they have a lower abuse potential and relatively lower adverse reactions (chiefly, death is a relatively common result in barbiturate overdoses) and interactions.