dr. ahmed m. alafeefy e-mail: [email protected] tel: 0507069896
TRANSCRIPT
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.