Transcript central nervous system

Dr. Heru Chen
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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
cerebra
pituitary
pons
medulla
cerebel
脑
Brain
optocele
Central Nervous System
heel of nervi spinales
spinal cord
cervical nerve
thoracic nerve
anterior of nervi spinales
nervi spinales
nervi lumbales
nervi sacrales
nervi coccygeus
Spinal cord
脊髓
Central
Nervous System
神经系统：外周神经系统
olfactory nerve
pathetic nerve
optic nerve
oculomotor nerve
abducent nerve
facial nerve
trifacial nerve
nervi statoacusticus
nervi glossopharyngeus
pneumogastric nerve
nervi hypoglossus
nervus accessorius
脑神经
nervi cerebrales
Central Nervous System
rami cutaneus
spinal ganflion
rami posterior nervi spinalis
rami anterior
heelpiece
postcornu
anterior angle
anterior root
trunk of spinal nerve
sympathetic ganglia
intercostal nerves
rami lateralis cutaneous
rami cutaneus anterior
脊神经
nervi spinales
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. Barbiturates
2. Benzodiazepines
3. Others
O
NH
O
NH
O
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 GABAA receptor. GABA is
the principal inhibitory neurotransmitter in the
mammalian CNS.
Barbiturates are derivatives of barbituric acid.
O
NH
O
NH
O
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 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 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 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
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
R
R1
O
N
R2
O
NH
O: replace with S
fast action
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.
H3C
N
N
N
Alprazolam (佳乐定）
Cl
N
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.