Transcript Central Sympathomimetics Agents

CNS Stimulants
1. Analeptics stimulate autonomic system (respiratory and circulation)
2. Methylxanthines (caffeine, theobromate and theophylline)
3. Central sympathomimetics agents
O
Analeptics
NH2
S
O
Provigil (Modafinil)
Atypical 1 norepinephrine receptor stimulant
Nacrcolepsy, sleep apnea
Adverse side effects: nervousness, anxiety and sleeplessness
O
+
N
ClH
3
2
4
Methylxanthines (Caffeine, theophylline and
theobromine) CNS stimulation is believed to be
linked to adenosine receptors
5N
1
O
R"
O
N7
5
8
9
Dopram (Doxapram HCl)
Respiratory stimulant, Overdose with
CNS depressant, chronic obstructive
pulmonary diseases (COPD)
and apneas.
N
4
6
3
N
R'
1N
R
2
O
O
R"
N7
5
8
9
N
Compound
Caffeine
Theophylline
Theobromine
R
CH3
CH3
H
4
6
3
N
R'
1N
R
2
O
R’
CH3
CH3
CH3
R”
CH3
H
CH3
Coffee, Tea
Tea
Cocoa
Caffeine is widely used CNS stimulant. It found in brewed coffee, brewed tea and
cola beverages. Dosage range for stimulation is 85 to 250 mg. Adverse side effects
include restlessness, anxiety and nervousness. At high dose, convulsion may occur.
Use to treat migraine and tension headaches (central vasoconstriction)
Theophylline has been used as CNS stimulant, used as bronchodilator.
Caffeine being more lipophilic than theophylline thus having higher brain
concentrations. Caffeine’s half-life (5 to 8 hours) and theophylline’s half-life (3.5 hours).
Mechanism of action: CNS stimulation (antagonize adenosine A1 and A2 receptors).
NH2
O
R"
N
N
N7
N
N
8
O
9
HO
N
OH
5
OH
Adenosine
4
6
3
1N
R
2
N
R'
Methylxanthines
O
Central Sympathomimetics Agents
H
+
-phenylethylamine
NH2
HSO4
Structure Activity Relationship (SAR)
Lower alkyl groups adjacent () increases CNS rather than peripheral activity
Branching generates a chiral center. The dextro(S) of amphetamine is 10 times
more potent than levo (R) isomer.
Hydroxylation of ring or () carbon decrease activity. Phenylpropanolamine
Halogenation (F, Cl, Br) of the aromatic ring decreases activity. Chloroamphetamine
has strong central serotoninergic activity.
Methoxy substitution cause dopaminergic activity (D2)
N-methylation increases activity (methamphetamine)
Mono substitution larger than methyl decrease activity
Di-N-methylation decreases activity
NH2
CH3 H
NH2
NH2
Cl
CH3
CH3
CF3
p-Chloroamphetamine
5-HT releasing agent
S (+)-Amphetamine
Fenfluramine
5-HT releasing
agent. Appetite
suppressant
NH2
HO
CH3
p-hydroxyamphetamine
NH2
MeO
CH3
P-methoxyamphetamine (PMA)
Weak CNS stimulant (10% potency)
Cathines Ephedra used as dietary supplement contain ephedrine and caffeine.
CH3
CH3
H
NHCH3
H
OH
(-)
H
H
NH2
H2N
H
HO
H
H
OH
HO
H
HO
CH3HN
H
Pseudoephedrine (-)
(+)
Norephedrine
CH3
CH3
H
(+)
(-)
(+)
Ephedrine
NHCH3
CH3
CH3HN
CH3
H
CH3
H
OH
H
CH3
NH2
HO
H
H2N
H
H
(+)
Norpseudoephedrine
OH
(-)
HO
H
CH3
O
NH2
H
Norephedrine
CH3
NH2
H
Khat (leaves eaten in Middle East)
H
+
NH2
HSO4
Benzedrine (Amphetamine Sulfate)
racemic mixture more cardiovascular effect
Dexedrine (Dextroamphetamine Sulfate and Dextroamphetamine Phosphate) (IV)
mechanism of action involves the release of Norepi to a smaller extent inhibition of
Norepi uptake at postsynaptic cleft (1)
Adderall (combination of salts saccharate, sulfate, aspartate)
Dextroamphetamine is strongly basic.
(S) configuration has fewer cardiovascular effects and 10 times more potent than
(R) as CNS stimulant.
Systemic acidosis can cause 60 to 70% of the drug to excreted unchanged.
-methyl group retards metabolism by MAO. What is the major route of
metabolism of dextroamphetamine?
Uses narcolepsy, Parkinson’s disease, attention deficient disorders (ADD), dieting.
Amphetamine Metabolism
HN OH
CH3
N-Hydroxyamphetamine
NH2
O
O
OH
CH3
CH3
Amphetamine
Phenylacetone
Benzoic acid
OH
NH2
HO
CH3
p-Hydroxyamphetamine
O
CH3
Hydroxy Ketone
Derivative
CH3
+
CH3
-
Cl
NH2
Desoxyn (Methamphetamine HCl)
Very highly abuse drug
Street name “Meth, Ice, or glass”
Uses same as amphetamine
+
NH
Cl-
Didrex (Benzphetamine HCl)
A decrease in activity.
Maintain Anorexiant activity ( receptor agonist)
H
+
+
O
NH
HN
-
Cl-
Cl
CF3
Tenuate, Tepanil (Diethylpropion HCl)
Anorexiant agent
Pondimin (Fenfluramine hydrochloride)
Sedation rather than excitation (serotoninergic)
In combination with phentermine (phen-fen)
Removed from market because heart valve
Damage 1997 (5HT2B)
H
O
N
NH2
HN
O
O
OCH3
Ritalin (Methylphenidate hydrochloride)
marketed as racemate
Its p-hydroxy metabolite blocks Norepi
reuptake and acts as postsynaptic agonist.
In the stomach the protonate form is
resistant hydrolysis.
Uses Narcolepsy or
attention deficit disorder (ADD).
Pemoline
Requires 3 to 4 weeks after
administration to elicit an effect.
Delay relayed to increase in
dopamine synthesis.
Trade name Cyclert discontinued
Liver toxicity
NH2
CH3
H
CH3
H
Ionamin (Phentermine Ion-Exchange Resin)
Diet supplement
HN
CH3
H
H
H
Didrex (Benzphetamine Hydrochloride)
Diet supplement ( agonist)
Central Sympathomimetic agents (Continue)
N
CH3
N
CH3
O
Plegine (Phendimetrazine)
Anorexiant
Cl
Merida (Sibutramine)
Anorexiant and Antidepressant