Dr. Ahmed M. Alafeefy E-mail: [email protected] Tel: 0507069896.

Dr. Ahmed M. Alafeefy

E-mail: [email protected]

Tel: 0507069896

My research group Hiking at Huolu Mountain

Medicinal Chemistry

Chapter 2. Central Nervous System Drugs

1. Anxiolytics, sedative-hypnotics2. Antiepileptics3. Antipsychotics4. Antidepressants5. Analgesics6. 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

medullapons

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 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

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+, 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.

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. Barbiturates2. Benzodiazepines3. Others

BarbiturateBenzodiazepines

NH

NHO

O

O

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 GABAA receptor. GABA is the principal inhibitory neurotransmitter in the mammalian CNS.

Barbiturates are derivatives of barbituric acid.

Barbiturates

NH

NHO

O

O

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 pKa = 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 CO2 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 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 usedIn order to avoid the invalidation of the injections, be careful the following

Avoid pre-formulation, sterilization by heatingshould be made in powder-injection, dissolved before used

4. It reacts with metal ions such as Cu2+, Hg2+, and Ag+,

for example, it reacts with Cu2+ 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

R2: CH3

fast action

O: replace with Sfast 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

NH

NO

O

O

R

R1

R2

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 GABAA 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 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.

SAR

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

N

NN

N

Cl

H3C

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.