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Chapter 2.6.
Central Nervous System Stimulants
中枢神经兴奋药
• Action mainly on cerebra, medulla oblongata and spinal cord
• Certain degree of selectivity
dosage ，
Action intensity ，
Action range ，
selectivity
Concept: central stimulants are drug that enhance the function of brain
Be caution when taking
• If overdose,strong stimulation will result in convulsion.– Over-inhibition danger to life
• Watching carefully the reaction of patients after taking drug. Be careful to control dosage
Classification based on the action sites
• Pallium stimulants (psychotic stimulants) – caffeine 、 methylphenidate
• Spinal cord stimulants – nikethamide 、 lobeline
• Nootropic drug – piracetam 、 meclofenoxate
Classification based on chemical structure and
resource• alkaloids caffeine• Derivatives of amide piracetam• phenylethylamine • others
N
N
N
N
O
O
. H2O NH2N
O
O
camellia
Caffeine
• trimethylxanthine
N
N
N
N
O
O
. H2O
Structure and Nomenclature • 1 ， 3 ， 7- 三甲基 -3 ， 7- 二氢 -1H - 嘌呤
-2 ， 6- 二酮一水合物• 3 ， 7-Dihydro-1 ， 3 ， 7-trimethyl-1H -
purine-2 ， 6-dione monohydrate
N
N
N
N
O
O
. H2O
1
3
7
Matrix
• -1H- purine -2 ， 6-dione
N
N
N
N
O
O
1
3
76
4
5H
N
N
N
N
O
O
H
H
H1
8
6 75
432 9
orientation of H trivial name
preparation• Indwell in coffee bean and tea
• Extracted from plant in the early years
• Nowadays, total synthesis
A cup of teaContains 50mg caffeine
In most people, 85-250 mg of caffeine acts as a cortical stimulant and facilitates a clear thinking and wakefulness, promotes an ability to concentrate. An increased dose leads to excessive stimulation.
N
N N
NH3C
CH3
CH3O
O
N
N N
NH
CH3
CH3O
O
N
N N
NH3C
CH3
HO
O
N
N N
NH
H
HO
O
The naturally occuring methylxanthines are:
Caffeine----coffee, tea
Theophylline----tea
Theobromine----cocoa
Caffeine Theophylline Theobromine Xanthine
Process for Total Synthesis
HCOOH
O
HO
N N
N
ON
OH
NH
NH
O
O
O ONaOH N
N
O
O NH
NaNO2, H2SO4
N
N
O
O NH
N OH Fe, HCl N
N
O
O
NH2
NH2
N
N
O
O
NH
NH2O
NaOH N
N
O
O
HN
N NaOH
N
N
O
O
N
N. H2O
(CH3)2SO4
1. pyrimidine ring
2. Purine ring
Semi-synthesis
Theophylline
methylation
N
N
O
O
HN
N NaOH
N
N
O
O
N
N. H2O
(CH3)2SO4
(7-methyl-theophylline)
caffeine
caffeine and sodium benzoate
• Sodium benzoate and caffeine• Aqueous solubility increases
because of intermolecular hydrogen bond
• Formulation of injection
N
N
N
N
O
O
-O OH
OH
Distinguished reaction
• Iodine testing reaction– reddish brown precipitate
[ C8H10N4O2 ]. HI. 2I2 + NaOH C8H10N4O2 + NaI + 2I2 + H2O
The precipitate dissolve in excess NaOH solution
C8H10NO2 + 2 I2 + KI + HCl . HI . 2 I2[ C8H10N4O2 ] KCl+
Distinguished Reaction
• Murexide reaction– For purine-like alkaloid （ oxidised
with condensation next ）
N
N
O
OONH4
N
N
N
O
O
O
NH3
×ÏÉ«
N
N
N
N
O
O
N
N
O
O
O
O N
N
O
O
HO
O+
KClO3, HCl
N
N
O
O O
HO
NN
O
O
O
OH N
N
O
O O
HN
NN
O
O
O
N
N
O
OOH
N
N
N
O
O
O
NH3
- H2O
Mechanism
• Inhibition the activity of phospho-diesterase ， decrease the decompose of cAMP.
• Enhancing the exciting process of pallium
Action
• Treatment of failure central respiration ， circulation ， nerve and psychotic depressant
• Weak action of heart excitation and diuresis
N
N
N
N
O
O
. H2O
Similar drugs
• Xanthine derivatives from nature– Difference in quantity and position of
substituted methyl
N
N
N
N
O
O
H
theobromine
N
N
N
N
O
O
H
theophyllineCaffeine
N
N
N
N
O
O
. H2O
Comparison of Pharmacological Action
• Central Excitation– Caffeine > theophylline > theobromine
• Relaxation of smooth muscle and diuresis– theophylline > theobromine > Caffeine
N
N
N
N
O
O
HN
N
N
N
O
O
HN
N
N
N
O
O
. H2O
Usage• Caffeine central excitation• theophylline smooth muscle relaxation diuresis and cardiotonic drug
• Theobromine less application
N
N
N
N
O
O
H N
N
N
N
O
O
HN
N
N
N
O
O
. H2O
1
3
76
4
5
Piracetam • Piracetam• 2-oxo-1-pyrrolidineacetamide • 脑复康• 吡乙酰胺
NH2N
O
O
Synthesis
CH3ONa NH3ClCH2COOEt
NH
ONNa
O NO
O
O
NO
NH2
O
Action · γ-lactam drugs for improving brain functions
– Directly action on pallium
– Action of activating, protecting and repairing nerve cells
– Improvement of cognition ability of slight and moderate dementia patients
– Invalidation for heavy dementia patients
• For treatment of dysmnesia and weak intelligence children caused by brain trauma
NH2N
O
O
Action target
• Adjustment via GABA channel
• Improving the release of acetylcholine from hippocampi, increaing the transmission of choline
Similar drugs
• Exchange substitutes at position 1 and 4
O
NN
O
pramiracetamaniracetam
N
O
O
NH2
oxiracetam
N
O
O
NH2
OH
1
4
O
N
O
O
Central sympathomimetic agents(Psychomotor stimulants)
Phenylethylamines central stimulant
Phenylpropylamine alcohol(PPA)
diethylpropion fenfluramine
Stay away from drug ， cherish your life
• Methylphenyl amine (ice sculpture)
H NH
• Ecstasy (MDMA)
H NO
O
H
