Central Nervous System Stimulants

The CNS stimulants achieve their effect either by the stimulation of nervous tissue through blocking
the actions of inhibitory cells or releasing transmitter substances from the cells or by the direct action of
the drugs themselves. These drugs include all of the amphetamines and cocaine. Nicotine and caffeine
also stimulate nervous tissue but to a much lesser degree (Hardman et al., 1996; Inaba & Cohen, 2007;
Schuckit, 1984).

A. Analeptics
-ranges from plant alkaloids to synthetic compounds.
-most are orally absorbed and has short duration of action.
-pharmacologic effect of these drugs are terminated through hepatic metabolism.

1. Picrotoxin
Picrotoxin is obtained from fishberry which block the action of GABA on chloride channel
(block the ion channel). It can cause convulsion.
Synonyms: cocculin, picrotoxinin(A.I)
Properties:
Bitter, colorless or white microcrystalline powder
Melting point: 203.5 C
Synthesis:
Picrotoxin is a toxin obtained from the seeds of the shrub Anamirta cocculus.
Uses:
As a research tool
Antidote in CNS depressant poisoning, especially in barbiturates.

2. Pentylenetetrazole (PTZ)
A pharmaceutical agent that displays activity as a central nervous system and respiratory
stimulant. It is considered a non-competitive gamma-aminobutyric acid (GABA)
antagonist.
Trade Names: Metrazol, Cardiazol Dicodid, Cardiazol Paracodina
Synonyms: pentetrazol, pentamethylenetetrazol
Properties:
White, crystalline powder or granular solid with a slightly pungent odor.
Bitter taste.
Uses:
Used in conjunction with the electroencephalograph to help locate epileptic
foci
Used to study seizure phenomenon and to identify pharmaceuticals that may
control seizure susceptibility

3. Modafinil
 Modafinil is a synthetic central nervous system stimulant with wakefulness-promoting
activity. Modafinil appears to inhibit dopamine reuptake, resulting in an increase in
extracellular dopamine. May improve cognitive function in certain clinical settings.
Trade Names: Provigil, Alertec
Synonyms: benzhydrylsulfinylacetamide, 2-[(diphenylmethyl)sulfinyl]acetamide
Properties:
White to off-white crystalline powder
Synthesis:
Benzhydrylthioacetamide are placed in a balloon flask and acetic acid and
H2O2 (about 110 volumes, 33%) are added. The mixture is left in contact for one
night at 40C. And water is then added; the CRL 40476 crystallizes. By
recrystallization from methanol, modafinil is obtained.
Uses:
Improving wakefulness in patients with excessive sleepiness associated with
narcolepsy or other sleep disorders.
In the treatment of ADHD, Chronic Fatigue Syndrome, depression, fatigue,
hypersomnia, narcolepsy, Obstructive Sleep Apnea/Hypopnea Syndrome and
Shift Work Sleep Disorder

4. Doxapram Hydrochloride
A central respiratory stimulant with a brief duration of action.
Trade Names: Dopram, Docatone
Synonyms: 2-Pyrrolidinone, 1-ethyl-4- (2-morpholinoethyl)-3,3-diphenyl-, monohy-
drochloride
Properties:
Odorless, white to off-white crystalline powder.
Synthesis:
Doxapram, (+)-doxapram and ()-doxapram enantiomers may be obtained by a
method comprising converting (Z)-butene-1,4-diol into the intermediate (Z)-4-
(diphenylacetyl-ethyl-amino)-but-2-enyl ester of acetic acid, and subsequently
inducing carbocyclization of the intermediate by reacting it with a strong base,
such as potassium hexamethyldisilazide or sparteine, to yield 1-ethyl-3,3-diphenyl-
4-vinyl-pyrrolidin-2-one, racemic or optically enriched form respectively. The
carbocyclization reaction may be also carried out in the presence of
tris(dibenzylideneacetone)dipalladium(0) and BINAP (2,2-
bis(diphenylphosphino)-1,1-binaphthyl) to obtain 1-ethyl-3,3-diphenyl-4-vinyl-
pyrrolidin-2-one in optically enriched form. The intermediate 1-ethyl-3,3-
diphenyl-4-vinyl-pyrrolidin-2-one may be further derivatized to yield doxapram,
(+)-doxapram or ()-doxapram enantiomers.
Uses:
Reverses respiratory depression from opiates without affecting pain relief.
Increases depth of respirations (tidal volume) by stimulating respiratory center
in CNS.
B. Methylxanthines
-purine derivatives that have in common a xanthine core molecule with methyl groups
attached in various combinations to nitrogens, at positions 1, 3, 7, or 9.
- bronchodilators used in the treatment of asthma and chronic obstructive pulmonary disease.

1. Caffeine
A methylxanthine naturally occurring in some beverages and also used as a
pharmacological agent. Caffeine's most notable pharmacological effect is as a central
nervous system stimulant, increasing alertness and producing agitation.
Trade Names: Vivarin, NoDoz, Cafcit, 357 HR Magnum
Synonyms: Methyltheobromine, Guaranine, 1,3,7-Trimethylxanthine
Properties:
Odorless, white needles or powder
Synthesis:
The first synthesized caffeine was successfully generated from the raw material in
1895 by a German chemist, Hermann Emil Fischer.
Uses:
Stimulates diuresis, relaxes smooth muscle
As the citrate salt, is used for the short-term management of apnea in
premature infants.
85 to 250 mg acts as a cortical stimulant and facilitates clear thinking and
wakefulness.

2. Theophylline
Theophylline has some medical use as a CNS stimulant, but its CNS stimulant properties
are encountered more often as sometimes severe, and potentially life-threatening, side
effects of its use in bronchial asthma therapy.
Trade Names: Respbid, Slo-Bid, Theo-24, Elixophyllin
Synonyms: 1,3-dimethylxanthine
Properties:
Bitter, odorless white crystalline powder.
Synthesis:

Uses:
 Diuretic, smooth muscle relaxant, bronchodilator, cardiac and central nervous
system stimulant activities.

3. Theobromine
Theobromine has very little CNS activity (probably because of poor physicochemical
properties for distribution to the CNS). The principle alkaloid in Theobroma.
Synonyms: 3,7-Dimethylxanthine; Diurobromine
Properties:
Bitter, odorless white crystalline powder.
Synthesis:
Theobromine is synthesized by reacting 3-methylxanthine disodium salt with
dimethyl sulfate by using acetone as solvent in the presence of sodium carbonate
and acidifying the mixture, cooled, filtering the solid, washing and drying.
Uses:
As a bronchodilator and as a vasodilator
Weaker diuretic activity and is also a less powerful stimulant of smooth muscle
than theophylline.

C. Psychomotor Stimulants (Central Sympathomimetic Agents)

-These drugs stimulate transmission at synapses that use epinephrine, norepinephrine,
dopamine, or serotonin as transmitters
-The term sympathomimetic is used because epinephrine is the primary transmitter in the
sympathetic nervous system, and these drugs stimulate sympathetic synapses to some extent
and mimic sympathetic arousal.

1. Amphetamine
A mixture of its two isomers (dextro- and levo-amphetamine). Readily absorbed orally and
by inhalation. It is resistant to metabolism by monoamine oxidase.
Trade Names: Adderall, Benzedrine
Synonyms: alpha-methyl-phenylethylamine, ()-1-phenyl-2-aminopropane
Properties:
Slowly volatile liquid with characteristic amine odor (similar to geranium
leaves) and an acrid taste.
Synthesis:
Amphetamine can be obtained in a 30% yield in a one-step synthesis by refluxing
phenylacetone in ethanol with ammonia, aluminum grit, and a small quantity of
mercuric chloride.
Uses:
Used in the treatment of ADHD and narcolepsy

2. Dextroamphetamine
Has more medical uses compared to its levorotatory isomer. Forms salts with sulfuric acid
and with phosphoric acid. The phosphate is more water-soluble is preferred if parenteral
administration is required
Trade Names: Dexedrine (sulfate salt)
 Synonyms: (+)-(S)-methylphenethylamine
Properties:
Colorless, volatile liquid with an amine taste. Acrid in odor.
Synthesis:
Starting from D-phenylalanine, dextroamphetamine sulfate and methamphetamine
hydrochloride were synthesized. The reaction sequence proceeds through three
intermediates, in which the absolute configuration of the asymmetric carbon atom
is changed but the relative configuration remains the same. Either product can be
obtained from a common intermediate by altering the reductive conditions
employed for the removal of a carbamate protecting group.
Uses:
Used in the treatment of ADHD and narcolepsy

3. Methamphetamine Hydrochloride
Methamphetamine is a central nervous system stimulant. It affects chemicals in the brain
and nerves that contribute to hyperactivity and impulse control. The smokable form is a
drug of abuse and is referred to as crank, crystal, crystal meth, ice, and speed.
Trade Names: Desoxyn
Synonyms: (2R)-N-methyl-1-phenylpropan-2-amine
Properties:
white crystalline powder
Synthesis:
Making it from ephedrine or pseudoephedrine is possible. The only difference
between methamphetamine and (pseudo)ephedrine is the alpha-hydroxy group. Reacting
your ephedrine with thionyl chloride replaces the OH with Cl to produce N-methyl-alpha-
chloroamphetamine as an intermediate. Hydrogenating this product is easy: use lithium
aluminum hydride, sodium borohydride, or even hydrogen gas with nickel or platinum
metal as a catalyst. The product of this step is N-methylamphetamine and HCl. Evaporate
off the water and you have methamphetamine hydrochloride.
Uses:
Used in the treatment of ADHD and narcolepsy
Used to treat obesity after other diets or medications have been tried without
successful weight loss.

4. Phentermine Ion-Exchange Resin and Phentermine Hydrochloride

It reportedly has pharmacological properties of both the (R)and (S)-isomers of
amphetamine. In the resin preparation (Ionamin), the base is bound with an ion-exchange
resin to yield a slow-release product; the hydrochloride (Wilpowr) is a water-soluble salt.
Trade Names: Ionamin, Wilpowr
Synonyms: ,-dimethylphenethylamine, 1-phenyl-2methylaminopropane.
Properties:
Colorless, mobile, oily liquid with an odor of that of amines
Synthesis:
 Uses:
As an appetite suppressant
Treat obesity (overweight) in people with risk factors such as high blood
pressure, high cholesterol, or diabetes.

5. Benzphetamine Hydrochloride
Benzphetamine Hydrochloride is the hydrochloride salt form of benzphetamine, a
sympathomimetic amine related to the synthetic agent amphetamine with central nervous
system (CNS) stimulating and anorexic properties.
Trade Names: Inapetyl, Didrex
Synonyms: N-benzyl-N-methyl-1-phenylpropan-2-amine;hydrochloride
Properties:
white crystalline powder
Synthesis:
Reaction of methamphetamine hydrochloride with benzyl chloride in water, in the
presence of an inorganic base and isolating benzphetamine of followed by
subsequent treatment with hydrochloric acid in an organic solvent in anhydrous
conditions and isolating benzphetamine hydrochloride salt.
Uses:
causes behavioral changes including euphoria, an increase in mental alertness
and excitement
Centrally acting anti-obesity product

6. Diethylpropion Hydrochloride
Diethylpropion is an appetite depressant considered to produce less central nervous system
disturbance than most drugs in this therapeutic category. It is also considered to be among
the safest for patients with hypertension.
Trade Names: Anorex, Tepanil
Synonyms: 2-(diethylamino)-1-phenylpropan-1-one
Properties:
When heated to decompose it emits very toxic fumes of hydrogen chloride and
nitrogen oxides.
Uses:
Anti-obesity and appetite-suppressant

7. Phendimetrazine Tartrate
Phendimetrazine is considered an effective anorexiant that is less abuse prone than
amphetamine.
Trade Names: Plegine, Bontril, Hyrex, Dyrexan
Synonyms: (2S,3S)-3,4-dimethyl-2-phenylmorpholine-L-(+)-tartrate
Properties:
White, odorless powder having a bitter taste.
 Synthesis:

Uses:
is a weight loss medication

8. Sibutramine
Sibutramine is said to be an uptake inhibitor of NE and 5-HT. These mechanisms fit its
structure. It is reportedly an antidepressant and an anorexiant drug. In October
2010,Sibutramine was withdrawn from Canadian and U.S. markets due to concerns that the
drug increases the risk of heart attack and stroke in patients with a history of heart disease.
Trade Names: Meridia, Reductil
Synonyms:1-(4-Chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl)cyclobutanemet-
hanamine
Properties:
White solid
Uses:
treatment of obesity
decreases calorie intake and increases energy expenditure

9. Methylphenidate Hydrochloride
has two asymmetric centers, so, there are four possible isomers. The threo racemate is the
marketed compound and is about 400 times as potent as the erythro racemate.
Methylphenidate appears to activate the brain stem arousal system and cortex to produce its
stimulant effect and, in some clinical settings, may improve cognitive function.
Trade Names: Ritalin
Synonyms: methyl 2-phenyl-2-piperidin-2-ylacetate;hydrochloride
Properties:
Odorless white crystalline powder. Metallic taste.
Uses:
used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD)
and narcolepsy.

10. Pemoline
has minimal sympathomimetic properties, but animal studies indicate it may work through
dopaminergic mechanisms. Pemoline has been withdrawn from the U.S. market because of
the agent's association with life threatening hepatic failure. Pemoline differs from other
stimulants in that it has very few symphatomimetic side effects, such as dry mouth, cardiac
stress, or dilated pupils. It does not posess the jitteriness of caffeine either.
Trade Names: Cylert, Tradon
Synonyms: 2-amino-5-phenyl-4(5H)-oxazolone
Properties:
Tasteless, White crystalline powder.
 Synthesis:
Using Sodium Hydroxide as the Base: A solution of guanidine freebase
(Prepared by mixing a solution of 6.1g (0.05 mol) of Guanidine Nitrate in 30 ml of
hot ethanol and a solution of 2g (0.05 mol) NaOH in 25 ml hot ethanol). 4.5g
(0.025 mol) of ethyl mandelate in 5ml of ethanol is added to this boiling mix, and
it is left at reflux for 30 minutes. The solution is cooled to room temperature, and
50 ml of cold distilled water is added. The solution is filtered and the precipitate is
washed with cold water and MeOH in small portions. The precipitated pemoline is
air dried on filter paper. Yield 90%, mp 256-257C (dec).
Uses:
Treatment for ADHD

D. Antidepressants
-Antidepressant therapy usually implies therapy directed against major depressive disorders
of the unipolar type and is centered on three groups of chemical agents: the MAOIs, the
monoamine reuptake inhibitors, and autoreceptor desensitizers and antagonists. Electroshock
therapy is another option. The highest cure or remission rate is achieved with electroshock
therapy. In some patients, especially those who are suicidal, this may be the preferred
therapy. MAOIs and monoamine reuptake inhibitors have about the same response rate
(60%70%).

a. Monoamine Oxidase Inhibitors

- are chemicals which inhibit the activity of themonoamine oxidase enzyme family. They
have a long history of use as medications prescribed for the treatment of depression. They
are particularly effective in treating atypical depression.

1. Phenelzine Sulfate
it irreversibly inactivates the enzyme or its cofactor, presumably after oxidation to the
diazine, which can then break up into molecular nitrogen, a hydrogen atom, and a
phenethyl free radical. The latter would be the active species in irreversible inhibition.
Trade Names: Nardil
Synonyms: (2-Phenylethyl)hydrazinsulfate
Properties:
Melts at temperatures greater than 25 C
Uses:
treats depression by restoring the balance of certain natural substances
(neurotransmitters) in the brain
used to treat depression, phobic disorders, and panic.

2. Tranylcypromine Sulfate
Tranylcypromine is a propylamine formed from the cyclization of the side chain of
amphetamine.
Trade Names: Parnate
Synonyms: ()-trans-2-phenylcyclopropylamine sulfate
Properties:
 Liquid.
Melts at 79-80 C at 1.50E+00 mm Hg
Uses:
treatment of major depression, dysthymic disorder, and atypical depression
useful in panic and phobic disorders

b. Monoamine Reuptake Inhibitors

- A monoamine reuptake inhibitor (MRI)[1] is a drug that acts as a reuptake inhibitor of
one or more of the three major monoamine neurotransmitters serotonin, norepinephrine,
and dopamine by blocking the action of one or more of the respective monoamine
transporters (MATs).

c. Tricyclic Antidepressants
- tricyclic antidepressants (TCAs) are also used for some forms of anxiety, fibromyalgia,
and the control of chronic pain. Tricyclic refers to the presence of three rings in the
chemical structure of these drugs.

1. Imipramine Hydrochloride
This drug is thought to work by increasing the serotonin activity in the brain.
Trade Names: Tofranil
Synonyms: Imipramine hydrochloride, 5-[3-(dimethylamino)propyl]10,11-dihydro-
5H-dibenz[b,f]azepine monohydrochloride
Properties:
white to off-white, odorless, or practically odorless crystalline powder.
Uses:
Used to treat depression.
Imipramine tablets are also used to treat enuresis (bedwetting) in children

2. Nortriptyline Hydrochloride
Nortriptyline is a SNERI31; the composite action of drug and metabolite is nonselective. It
is a selective (NET) inhibitor.
Trade Names: Aventyl, Pamelor
Synonyms:3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)Nmethyl-1-prop-
anamine hydrochloride, 5-(3-methyl-aminopropylidene)-10,11-hydro-5H-
dibenzo[a,d] cycloheptene hydrochloride
Properties:
White to off-white powder with slight, characteristic odor.
Uses:
used for short-term treatment of various forms of depression

d. Selective Serotonin Reuptake Inhibitors

- SSRIs affect the chemicals that nerves in the brain use to send messages to one another.
These chemical messengers, called neurotransmitters, are released by one nerve and
taken up by other nerves. Neurotransmitters that are not taken up by other nerves are
taken up by the same nerves that released them. This process is termed "reuptake." SSRIs
 work by inhibiting the reuptake of serotonin, an action which allows more serotonin to be
available to be taken up by other nerves.

1. Fluoxetine
The first highly specific serotonin uptake inhibitor. It is used as an antidepressant and often
has a more acceptable side-effects profile than traditional antidepressants.
Trade Names: Prozac
Synonyms: N-Methyl-gamma-(4-(trifluoromethyl)phenoxy)benzenepropanamine
Properties:
White crystalline powder/crystals.
Uses:
treatment of major depressive disorder (including pediatric
depression), obsessivecompulsive disorder , bulimia nervosa, panic disorder

2. Paroxetine
A very highly selective SERT.
Trade Names: Paxil, Aropax
Synonyms: (3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine
Properties:
Odorless, off-white powder.
Uses:
effective antidepressant and anxiolytic

3. Sertraline
Sertraline affects chemicals in the brain that may be unbalanced in people with depression,
panic, anxiety, or obsessive-compulsive symptoms.
Trade Names: Zoloft
Synonyms:(cis-1S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthale-
namine hydrochloride
Properties:
white crystalline powder
Synthesis:

Uses:
treating depression, obsessive-compulsive disorder (OCD), panic disorder,
and post-traumatic stress disorder (PTSD).
 also used for treating social anxiety disorder and premenstrual dysphoric
disorder (PMDD)

e. Selective Norepinephrine Reuptake Inhibitors

- A class of chemical compounds that selectively, to varying degrees, inhibit the reuptake
of norepinephrine by the presynaptic neurons and are posited to exert their antidepressant
effect by this mechanism.

1. Nisoxetine
Most activity resides in the -isomer.
Synonyms: 3-(2-methoxyphenoxy)-N-methyl-3-phenylpropan-1-amine
Properties:
Boiling Point: 404.840.0 C at 760 mmHg
Uses:
widely used in scientific research as a standard selective noradrenaline
reuptake inhibitor.

2. Reboxetine
Most of the activity of reboxetine resides in the S,S-isomer (The marketed compound is RR
and SS.)
Trade Names: Edronax, Norebox, Prolift, Solvex, Davedax or Vestra.
Synonyms: (2S)-2-[(S)-(2-ethoxyphenoxy)-phenylmethyl]morpholine
Properties:
Melting point: 170-171 C (Mesylate salt)
Uses:
used in the treatment of clinical depression, panic disorder and ADD/ADHD

f. Newer (Nontricyclic) Nonselective 5-HT and NE Reuptake Inhibitors

1. Venlafaxine
Venlafaxine is a synthetic phenethylamine bicyclic derivative with antidepressant activity.
Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors
of neuronal serotonin and norepinephrine reuptake and weak dopamine reuptake inhibitors.
This agent may reduce hormone-related vasomotor symptoms.
Trade Names: Effexor, Effexor XR
Synonyms: 1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol
Properties:
Melting Point: 215-217 C (Hydrochloride salt)
Synthesis:
 Uses:
it is often effective for depression not responding to SSRIs
prescribed for the treatment of clinical depression and anxiety disorders.

g. Selective Serotoninergic Reuptake Inhibitors and 5-HT2A Antagonists

1. Trazadone
a serotonin uptake inhibitor that has been shown to be effective in patients with major
depressive disorders and other subsets of depressive disorders.
Trade Names: Desyrel, Oleptro
Synonyms:2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-
a]pyri-din-3-one
Properties:
white, odorless crystalline powder
Synthesis:
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Uses:
useful in depressive disorders associated with insomnia and anxiety.
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