Central nervous system stimulants
• compounds stimulating mental functions and physical performance
1. Phenylethylamine and phenylisopropylamine derivatives
2. Modafinil
3. Purine alkaloids
4. Compounds with tropane scaffold
● different concept to those of Ashutosh Kar, Medicinal Chemistry,
Anshan, Tunbridge Wells, UK, 2006, Chapter 8, pp. 194-209
© Oldřich Farsa 2011
1. Phenylethylamine and phenylisopropylamine derivatives
• natural catecholamines analogues
OH
OH N
OH
R
H
NH2
CH3
R = H
noradrenaline
R = CH3
adrenaline
amphetamine
Phenylethylamine and phenylisopropylamine derivatives
= indirect adrenergics – do not interact directly with adrenergic
receptors in the brain but inhibit reuptake of catecholamines or increse
their release from synapses; some of them act similarly also in
serotoninergic system
•centrally stimulating and anorectic effects
-OH group in α-position toward the aromatic ring is missing or O is the
part of a cycle (morpholine)
-OH group on the benzene ring are missing or etherified
phenylethylamine moiety can also be a part of a cycle
N
H
R
1
R
1
R
2
•supression of fatigue, feelings of hunger and thirst, increase of performance
•mobilization of energy reserves of organism
•indications: narcolepsy, obesity (obsolete)
•overdosage: total exhausting, dehydratation, circulation breakdown
•see further centrally acting anobesics (anorectics)
NH2
N
O
CH3
H
2-phenyl-3-
methylmorpholine
phenmethrazine
(R,S)-1-phenyl-2-aminopropane
amphetamine
1. Phenylethylamine and phenylisopropylamine derivatives
Compounds used as therapeutics
1. Phenylethylamine and phenylisopropylamine derivatives
Compounds used as therapeutics
H
H
N
H
O
CH3
O
methylphenidate
•for better concentration e.g. in childern with some form of autistic disorder
•kinetic disorder
Concerta ® , Ritalin ® , Medikinet ®
Phenylethylamine and phenylisopropylamine derivatives
Psychotropic compounds of amphetamine type
•belong among „hard drugs“
•physical addiction
CH3
N
CH3
H
(S)-2-methylamino-1-
phenylpropane
N-methylamphetamine
(S)-methamphetamine
syn. pervitine (as hydrochloride for
i.v. application); speed, crank,
crystal, crystal meth (base for i.
nas. administration – also
racemate)
•USA, CZ
CH3
N
CH3
H
O
O
2-(methylamino)-1-(3,4-
methylenedioxyphenyl)propane
3,4-methylenedioxymetamphetamine
ecstasy
syn. MDMA, Adam, XTC, „E“
•so called dancing drug
•hallucinogenic effect (5HT2A rp.)
•Europe
Phenylethylamine and phenylisopropylamine derivatives
Psychotropic compounds of amphetamine type
2-(ethylamino)-1-(3,4-
methylenedioxyphenyl)propane
3,4-
methylendioxyetamphetamine
MDEA
syn. MDE, Eve
2-(methylamino)-1-(3,4-
methylenedioxyphenyl)butane
MBDB
syn. Eden, methyl J, MDP2B
•Sweden
CH3
N
H
O
O
CH3 N
CH3
H
O
O CH3
Phenylethylamine and phenylisopropylamine derivatives
Psychotropic compounds of amphetamine type
2-amino-1-(3,4-
methylendioxyphenyl)propaner
tenamphetamine
syn. MDA, love drug, love pill
Y = O
2-amino-1-(4-methoxyfenyl)propan
paramethoxyamphfetamine
syn. PMA, 4-MA
Y = S
2-amino-1-(4-methylsulphanylphenyl)propane
4-methylthioamphetamine
syn. 4-MTA
•NL, UK, D, AU since the end of 1990th
CH3
N
H
O
O
H
CH3
N
H
Y
CH3
H
Synthesis of methamphetamine
CH3
OH
N
CH3
H
CH3
N
CH3
H
(1R or
1S,2S)-1-fenyl-2-methylaminopropane-
1-ol
(-)-ephedrine, (+)-pseudoephedrine
[HI]
I2, P
(I2, HPO2)
(S)-1-phenyl-2-methylaminopropane
(S)-methamphetamine
Phenylethylamine and phenylisopropylamine derivatives
Psychotropic compounds – 3,4-dihydrooxazole (2-oxazoline)
derivatives
O
N
NH2
CH3
2-amino-5-phenyl-4-methyl-4,5-dihydro-1,3-oxazole
4-methylaminorex
O
N
NH2
O
2-amino-5-phenyl-1,3-oxazole-4(5H)-one
pemolin
•formerly circulation and respiration stimulant
2. Modafinil
2-[(diphenylmethyl)sulphinyl]acetamide
modafinil
↑ vigility and mental acuity during the day
•treatment of narkolepsy and hypersomnia
•mode of action unclear
Vigil® tbl.
S
O
NH2
O
3. Purine alkaloids = „methylxanthins“
N
N
N
N
O
O
R
1
R
2
R
3
R1
= R2
= R3
= -CH3 caffein
R1
= R2
= -CH3, R3
= -H theopylline
R1
= -H, R2
= R3
= -CH3 theobromine
•occurrence in plants (Coffea, Camelia, Paulinia, Theobroma …)
•produced in most synthetically
•CNS stimulant (most caffeine), diuretic, bronchodilatatory (most theophylline)
effects
•mode of action: adenosine receptors A1
inhibition, phsphodiesterase inhibition,
catecholamines release
4. Compounds with tropane scaffold
N
CH3
O
CH3O
O
O
H
H
H
H
methyl-(1S,2R,3S,5S)-3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1]octan-2-carboxylate
cocaine
Cocaini hydrochloridum PhEur
•semisynthetic preparation from Erythroxylon coca leaves extract
•inhibits reuptake of catecholamines ⇒ indirect α1-sympathomimetic
•CNS stimulation, euphoria; constriction of peripheral vessels , ↑ blood pressure
•strong psychical addiction
•local-anaesthetic activity, sometimes used in ophthalmology
•a standard for determination of superficial anaesthetic activity of potential local anaest
Cognitive functions enhancers
≈nootropics, neuroanabolics
Cognitive functions: learning, comprehension, speech, judgement
• improve also attention and vigility of consciousness
• used in decrease of these functions due to brain ischemia in injuries and
dementias
• structurally heterogenic group, many modes of action possible
• in contrary to previous group the effect begins slowly after several weeks of
administration
Cognitive functions enhancers classification
1. Racetams
2. Cholinergics acting in CNS
3. Phenoxyalkanoic acids derivatives
4. Compounds of other structures or modes of action
Cognitive functions enhancers
1. Racetams
• contain pyrrolidin-2-one (γ-butyrolactame) fragment
N
H
O
•influence glutamate neurotransmission
•increase glucose utlization by brain tissue
Cognitive functions enhancers
1. Racetams
N O
NH2
O
N O
NH2
O
CH3
H
2-(2-oxopyrrolidin-1-yl)acetamide
piracetam
Geratam®
tbl., Nootropil®
tbl.,
Oikamid ®
cps., Kalicor®
cps. …
•low hydrophobicity ⇒ low
penetration into brain ⇒ high
doses necessary (1200 mg single
dose)
•low toxicity
(R,S)-2-(2-oxopyrrolidin-1-
yl)butanamide
etiracetam – cognitive function
enhancer
pure (S)-(-)-izomer – levetiracetam
antiepileptic of novel mode of action
and a lead compound of a whole novel
group
Keppra®
tbl.
Cognitive functions enhancers
Racetams
N
N
H
O
N
CH3
CH3
CH3
CH3
O
N
NH2
O
O OH
2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide
oxiracetam
N-[2-(diisopropylamino)ethyl]-2-(2-
oxopyrrolidin-1-yl)acetamide
pramiracetam
Cognitive functions enhancers
Racetams
CH3
CH3
NH
N
O
O
N
O
CH3
O
O
N-(2,6-dimethylphenyl)-2-(2-
oxopyrrolidin-1-yl)acetamide
nefiracetam
•Betzing et al. 1982
•close structural analogue of
lidocaine
•some antiepileptic and
antidysrythmic activity
1-(4-methoxybenzoyl)pyrrolidin-2-one
aniracetam
•also antiradical activity
Cognitive functions enhancers
Racetams
N
N O
N N
O O
1-phenyl-3,3-bis(pyridine-4-ylmethyl)-
1,3-dihydroindole-2-one
linopirdine
• treatment of Alzheimer disease (AD)
tetrahydro-3H-pyrrolizine-3,5-dione
rolziracetam
Cognitive functions enhancers
Racetams
Protirelin – synthetic thyreotropin-releasing hormone (TRH)
•a hormone of hypothalamus stimulating thyreotropine and prolactine synthesis in
hypophyse
•also neurotransmitter in CNS taking part in food intake and energy metabolism
control etc.
protirelin
5-oxoprolyl-histidyl-prolinamide
Protirelinum PhEur
•structure elucidated 1969, used since 1976
•administered p.o.
•used as cognitive functions enhancer for treatment of consequences of brain and
spinal cord damage and neurodegenerative diseases (Alzheimer, Parkinson)
N
O
NH2
O
N
H
N
O NH
N
H
O
Cognitive functions enhancers
2. Cholinergics acting in CNS
•compounds ↑ availability of t acetylcholine
in CNS
•mode of action: cholinesterases inhibition
N
NH2
O
N
O
OH
CH3
CH3
9-amino-1,2,3,4-tetrahydroaridine
tacrine
galantamine
•alkaloid isolated from bulbs of
Galanthus woronovii, G. elwesii
and others (Amarylidaceae)
Reminyl®
tbl.
•AD treatment
Cognitive functions enhancers
2. Cholinergics acting in CNS
O
O
O
N
CH3
CH3
O
O
N
CH3
CH3
N
CH3
CH3
CH3
3-[(1S)-1-(dimethylamino)ethyl]phenyl-N-
ethyl-N-methylcarbamate
rivastigmine
Exelon®
cps., Pronetal®
cps.
2-[(1-benzylpiperidin-4-yl)methyl]-
5,6-dimethoxyindane-1-on
donepezil
Aricept®
tbl.
•AD treatment
Cognitive functions enhancers
3. Phenoxyalkanoic acids derivatives
O
Cl
O
O
N
CH3
CH3
2-dimethylaminoethyl-2-(4-chlorphenoxy)acetate
meclofenoxate
N
S
OH
OH
S
CH3
N
OHOH
CH3
N
N
O
O
H
CH3
CH35-[({[5-hydroxy-4-(hydroxymethyl)-6-methylpyridi
ne-3-yl]methyl}dithio)methyl]-4-(hydroxymethyl)-
2-methylpyridine-3-ol
(+)-cis-
11a-ethyl-2,3,4,5,11a,11b-hexahydro
-1H-3a,9b-diazabenzo[cd]fluoranthen
-10-carboxylic acid ethyl ester
pyritinol
•structural analogue of vitamin B6 –
pyridoxol: 2 molecules linked with
disulfide bridge
Encephabol®
por. sus., Enerbol®
tbl.
vinpocetine
•derived from alkaloids of Vinca species
•improves brain metabolism,↑
consumption of O2
and glucose by brain
tissue
Cavinton®
tbl.
Cognitive functions enhancers
Compounds of other structures or modes of action
Halucinogens
= psychotomimetics, psychedelics, psychodysleptics
• cause „a condition similar to psychosis“
• cause changes of thinking, perception, mood, posture
• cause neither abuse nor addiction, do not stimulate CNS similarly to
amphetamines (O´Brien 2001)
• stimulate serotonine 5HT2A receptors in frontal cortex
„To sink in hell or sour angelic,
you‘ll need a pinch of psychedelic.“
Humphry Osmond 1957
Halucinogens classification
1. Compounds with tryptamine fragment in the molecule
1.1 Ergolines
1.2 Simple tryptamine derivatives
2. Phenylakylamine derivatives
3. Oxazole and isoxazole derivatives
Compounds with tryptamine fragment in the molecule
1.1 Ergolines
N
H
N
CH3
N
O
CH3
CH3
H
H
A B
C
D
5
8
D-LSD
Lysergic acid diethylamide (LSD)
syn. lysergide, Heavenly Blue, Wedding
Bells…
Lysergsäure Diethylamid ⇒ LSD-25
•prepared by Stoll and Hofmann in 1938 in
the frame of niketamide analogues research,
the effect found accidentally 16th
April1943
•effective dose ≥ 25µg
•acts on serotinine receptors
N
N
CH3
CH3
O
ninotinic acid diethylamid
nikethamide
•respiratory and circulation analeptic (obsolete)
Compounds with tryptamine fragment in the molecule
1.2 Simple tryptamine derivatives
• halucinogenic alkaloids of animals, plants and mushrooms
N
H
N CH3
CH3
R
1
R
2
P
O
OH
OH
O
R1
R2
-H -H
-H -OH
-H
-OH -H
-H -OCH3
bufotenin Bufo alvarius,
Anadenanthera
N,N-dimethyltryptamine (DMT)
Anadenanthera (Fabaceae)
psilocybine
Psilocybe mexicana
psilocin
Psilocybe mexicana
5-methoxydimethyltryptamine
(5-MeO-DMT)
Bufo alvarius
Compounds with tryptamine fragment in the molecule
1.2 Simple tryptamine derivatives
• psilcybin is a prodrug of psilocine
N
H
N CH3
CH3
O
P
OH
O
OH
N
H
N CH3
CH3
OH
alkaline phosphatase
- H3PO4
psilocybine
psilocin
•alcaline phosphatase is active in GIT, kidneys and blood
•psilocin as itself is not absorbed from GIT
2. Phenylalkylamin derivatives
NH2
O
CH3
O
CH3
O
CH3
NH2
O
CH3
R
CH3
O
CH3
2-amino-2-(3,4,5-
trimethoxyphenyl)ethane
mescaline
Lophophora williamsii,
Trichocereus peruvianus
R=-CH3 2-amino-1-(2,5-dimethoxy-4-
methylphenyl)propane
DOM
R=-Br 2-amino-1-(4-bromo-2,5-
dimethoxyphenyl)propane
DOB
R=-I 2-amino-1-(4-jodo-2,5-
dimethoxyphenyl)propan
DOI
• highly active synthetic
halucinogenes used for 5-HT
receptors research etc.
3. Oxazole and isoxazole derivatives
O
N
H
O
NH2
O
OH
N
H
O
O
NH2
O
OH
O
N
OH
NH2
2-amino-2-(2-oxo-2,3dihydrooxazole-5-yl)acetic
acid
muscazone
•hallucinogen
2-amino-2-(3-oxo-2,3-
dihydroisoxazole-5yl)acetic
acid
ibotenic acid
•glutamate receptor agonist
•agitated toxic delirium
fly mushroom Amanita muscaria, panther mushroom A. pantherina
3-hydroxy-5-
aminomethylisoxazole
muscimol
•GABA receptor agonist
•weak sedative