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

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.

Central Nervous System 脑 cerebra cerebel optocele Brain medulla pons pituitary

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

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

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

Chapter 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

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.

Ligand-gated ion channels The Ligand-gated ion channels are 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 +, Ca 2+, 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.

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

Based on chemical structures, this class of drugs can be divided into three groups: 1.Barbiturates 2.Benzodiazepines 3. Others Barbiturate Benzodiazepines

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.

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 GABA A receptor. GABA is the principal inhibitory neurotransmitter in the mammalian CNS. Barbiturates are derivatives of barbituric acid.

Barbiturates

Add Hydrogen

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 pK a = 7.9

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

2.The sodium solution absorbs CO 2 and the free drug precipitates from the solution, Suggestion: it cannot be exposed long in the air.

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

When 10% sodium solution is placed at 35 o C, 22% of the drug decomposes in one month. If it is stored at 1 o C 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

4.It reacts with metal ions such as Cu 2+, Hg 2+, and Ag +, for example, it reacts with Cu 2+ forming a purple color precipitate.

It reacts with silver nitrate forming a white precipitate.

Chemical synthesis of Amobarbital (from Diethyl malonate)

Metabolism of Amobarbital It metabolizes in the liver

Clinical use of Amobarbital As sedative-hypnotics, and Antiepileptics

SAR of barbituates R 2 : CH 3 fast action O: replace with S fast action If R (R 1 ) = H, no activity; it needs to be 2-5 carbon chains or 1 phenyl group The sum of R and R 1 needs to be 4-8

Long-term relief barbituates Barbital Phenobarbital

Mid-term relief barbituates amobarbital cyclobarbital

Short-term relief barbituates pentobarbital secobarbital

Super short-term relief barbituates hexobarbital thiopental sodium

The benzodiazepines are 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 GABA A as agonist. They began to be widely prescribed in the 1960s and 1970s.

Naming

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

Chlordiazepoxide is the first member of the benzodiazepines synthesized.

Diazepam (Valium) widely used for several anxiety states

Chemical synthesis

Properties of Diazepam 1.Hydrolysis At 37 o C 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.

SAR

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

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.