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Central Nervous System Stimulants 145
Other Xanthine Derivatives
(i) Aminophylline (phyllocontin®): 3, 7-dihydro-1, 3-dimethyl xanthine
Aminophylline is synthesized from theophylline and ethylenediamine treatment in ethanol. It
is used in the treatment of congestive heart failure, in asthma and cardiac paraxymol dyspnea.
(ii) Etofylline (bio-phyllin®): 7-(2-hydroxyethyl)-theophylline. Etofylline is considered a better
tolerable drug than its parent drug theophylline.
9.5.4 Cocaine Related CNS Stimulating Agents
Cocaine is chemically 2R-Carbomethoxy-3.S benzyloxy-1 R-tropane. It is naturally occurring alkaloid
obtained from the plant of erythroxyloncoca species, (described in local anaesthetics) and moiety
detailed in opioid analgesics). Cocaine possesses CNS stimulants activity in addition to vasoconstriction
action and local anaesthetic activity. Cocaine containing preparations are available in the market,
vincoca and soft drinks Coca-Cola. Cocaine is therapeutically useful agents as 5-HT
3
and serotonin
antagonistic. Cocaine is marked to block re-uptake action of norepineprine, serotonine and dopamine
therefore increase the level of neurotransmitters in synaptic cleft, thus exhibit CNS stimulant activity.
9.5.5 Miscellaneous CNS Stimulants Agents
(i) Sibutramine (Medridia®): Sibutramine is norepinephrine and 5-HT reuptake inhibitor. It is
reported as antidepressant and anorexiant agent. Sibutramine is widely used in the control of obesity.
C
Cl
C
H
2
C
H
2
CH
2
HC
2
CH
CH
N
HC
3
HC
3
CH
3
CH
3
Fig. 9.16: Sibutramine.
(ii) Penoline (Cylert®): 2-amino-5-phenyl-4-(5H)-oxazolone
Fig. 9.17
Condensation
Ethyl ester of mandelic acid
NH
2
O
N
H
O
Pemoline
CH — COOC H
25
OH
+
HN—C—NH
22
CH
Guanidine
Synthesis:
146 A Textbook of Medicinal Chemistry
Pemoline is nor-epinephrine and dopamine re-uptake inhibitors therefore it increases the rate of
synthesis of dopamine. Pemoline is used as potent CNS-stimulating agents.
Synthesis:
9.5.6 Newer Agents
1. Modafinil (Provigil®): D-modofinil is derivative of non-amphetamine moiety. It is approved
for the use in Nacrolapsy. It is more effective than amphetamine with lower incidence of side
effects.
S
O
C
NH
2
O
Fig. 9.18
2. Pramipexole: N-Propyl-tetrahydro-1, 3-benzothiazole-2,6-diamine
S
N
NH
2
N
H
HC
3
Fig. 9.19
Pramipexole is dopamine receptor agonist. It is used as CNS stimulant as well as in the treatment of
Parkinsonism disease.
1. Tolcapone: (3, 4-dihydroxy-5-nitrophenyl) (4-methyl-phenyl) methanone.
C
O
CH
3
HO
HO
NO
2
Fig. 9.20
Tolopone is catechol-o-methyltransferase inhibitor. Tolcapone is basically used in the treatment of
Parkinson’s disease.
Central Nervous System Stimulants 147
9.6 METABOLIC PATTERNS OF SOME CNS STIMULANTS AGENTS
(i)
Fig. 9.21
C
NH
2
H
HC
3
C
CH
3
O
C
CH
3
O
C
OH
COOH
(+) Amphetamine
Benzoic acid
9.7 ANALEPTICS OR RESPIRATORY STIMULANTS
Analeptic is the category of the drugs that possesses the stimulatory effects on the respiratory and
vasomotor centres situated in the medulla of brain. Analeptics are concerning primarily used as
antagonist in the overdose cause sedative and hypnotics. While at the small dose of therapeutic
(ii)
N—CH
3
C — OCH
3
N
C—OH
Cocaine
Benzoyl-ecgonine
Hydrolysis of
benzoyl ester
Hydrolysis of
methyl esters
Ecgonine methyl esters
O
OH
HC
3
OH
N
HC
3
Ecgonine
O
O
O
O
N—CH
3
OCH
3
O
OH
O
O
148 A Textbook of Medicinal Chemistry
action, they can stimulate other portion of centre nervous system. Further, in minor overdose they
lead a number of undesirable side effects like stimulation of cardiovascular system, convulsions,
vomiting, etc.
1. Doxapram (Doxapril®): 1-ethyl-4-(2-morpholinoethyl)-3, 3-diphenyl-2-pyrrolidinone.
Doxapram is a potent analeptic drug. It increases the rate and depth of respiration. It is used in the
treatment of post-operative respiratory depression condition.
CH — CH — N
22
O
N
CH
25
O
Doxapram
Fig. 9.22
C—C N
H
+
N
CH
52
Cl
C—C N
N
CH
52
(Sodium amide)
NaNH
2
N
CH
52
CH — CH — N
22
O
O
C — COOH
N
CH
52
(Acid hydrolysis)
HSO
24
(1-ethyl-3-pyrrolidinyl)
diphenylacetonitrile
Diphenylacetonitril
1-ethyl-3-chloropyrrolidine
(Phosphorus
tribromide)
(i) PB
3
r
O
(ii)
H—N
Doxapram
(Morphline)
Fig. 9.23
Synthesis:
Central Nervous System Stimulants 149
2. Almitrine (Duxil®): -2, 4-bis (allylamino)-6-[4-[bis-p(fluorophenyl) methyl]-1-piperazinyl-s-
triazine.
CH — N N
NH — CH — CH CH
22
NH — CH — CH CH
22
F
F
N
H
N
Fig. 9.24
Almitrine is a potent analeptic drug. It has similar properties like doxapram. It increases the rate and
depth of respiration. It increases the blood circulation in alveoli for better pulmonary ventilation.
3. Nikethamide (Corazone®): N, N-diethyl Pyridine-3-carboxamide.
Nikethamide is nicotinic acid derivative. It is considered a weak analeptic, used as respiratory
stimulants.
CON
CH
25
CH
25
N
Fig. 9.25
Nikethamide is synthesized from nicotinic acid and Benzene-sulfonic acid.
Synthesis:
+
HO—SO
2
C—O—SO
2
Dehydration
O
SO N
2
CH
25
CH
25
Diethyl benzene
sulphonamide
(Exchange reaction)
C—N
CH
25
CH
25
Nicotinic acid Benzene-sulphonic acid
N
COOH
N
N
O
Fig. 9.26
— H
2
O
150 A Textbook of Medicinal Chemistry
EXERCISE
1. Classify CNS-stimulating agents.
2. Explain the chemistry of xanthine derivatives of CNS stimulants.
3. Write the synthesis of the following drugs, write mechanism of action also.
(i) Caffeine
(ii) Dextroamphatamine
(iii) Diethyl propione
(iv) Nikethamide
4. Give a note on Analeptics. Write the synthesis of any one analeptic drug.
5. What are the structural requirements of amphetamines? Explain.
6. Discuss the drugs which come in the anorectics or appetite suppressants.
7. Discuss the cocaine related agents as CNS stimulants.
8. Give a note on sibutramine as CNS stimulants.
Antipsychotic Drugs 151
10
Antipsychotic Drugs
10.1 INTRODUCTION
Schizophrenia is characterized by a severe, long life, idiopathic psychiatric disorder with multigenic
component. It is constructed by severe thoughts and disorders called psychoses. Psychosis is
characterized by illogical, delusional or paranoid thoughts. It is clinically seen that its occurrence
lead onset its early adulthood stage with remissions to throughout life. There are no pathogenomic
syndrome features. The syndrome is commonly seen at late adolescence stage, further social
withdrawal, perception disturbance to recurrent delusions and hallucinations. Patient may get covered
with positive symptoms as well as negative symptoms but negative symptoms predominate in 1/3
population of schizophrenic patients, are associated poor long-term outcomes and poor response to
drug treatment.
Schizophrenia is further classified into the subcategories as given below.
Table 10.1: Schizophrenia subtypes
Type Salient Features
1. Catatonic type Change in motor activity, negativism, echolalia and/or echopraxia
2. Paranoid type Delusion, negative thoughts
3. Disorganized type Disorganized speech, behaviour superficial affects
4. Residual type Absence of delusion, hallucination, motor disturbance
10.2 CAUSES OF SCHIZOPHRENIA
Genetic causation is an evidently proof that is responsible for schizophrenia, genes includes,
neurogulin-1, dysbindin, proline dehydrogenase, D-amino oxidase activator, COMT (Catechol-o-
methyl transferase), nevregulin-1, dysbindin and D-amino-oxidase activator involves in glutamatergic
function further stimulate N-methyl-D-Aspartate (NMDA), in the concerning of treatment for D
2
-
receptors and possess much higher affinity for the D
4
receptors than D
2
-receptors.
152 A Textbook of Medicinal Chemistry
10.2.1 Adverse Effects
1. EPS (extrapyramidal symptoms): include Parkinson-like symptoms
2. Tradive pyskinesia
3. Neuroleptic malignant syndrome
4. Seizures
5. Sedation
6. Cognitive impairment
7. Anticholigergic effects
8. Cardiovascular effects
9. Sexual side effects and hyperprolactemia.
10. Weight gain
11. Haematological side effects
12. Hepatic effect
13. Dermatological side effects.
Possible mechanism involved in mediated glutamate responce would be therapeutic target for the
treatment. While COMT involves to deactivate the excess action of dopamine from the synapse.
10.3 ANTIPSYCHOTIC AGENTS
Antipsychotic agents are those which are used to treat acute and for maintenance of schizophrenia.
Antipsychotic agents are effective in the treatment of hallucinations, delusions and thought disorders.
10.3.1 Mechanism of Action
Antipsychotic drugs are prominent to bind dopamine D
2
/D
3
receptors. Newer atypical antipsychotic
agents also have ability to bind D
2
receptor and block them. All neuroleptics bind to dopaminergic
sites, however newer typical antipsychotic drugs may involve NMDA receptor blocked, α
1
and α
2
non-adrenergic activity.
Conventional neuroleptics like chlorpromazine and thioridazine are anticholinergic agents and
show sedative properties while higher potency of antipsychotics, some drugs haloperidol, perphenazine
are more likely to induce extrapyrimidal side effects. (EPS: extrapyrimidal symptoms), while
Benzodiazipines has greater potency towards 5HT
2
receptors.
10.4 CLASSIFICATION
1. Phenothiazines (Tricyclic Neuroleptics)
S
N
1
2
3
4
5
6
7
8
9
10
R
1
R
2
Fig. 10.1: Basic nucleus of phenothiazine.
Antipsychotic Drugs 153
S. No. Derivatives Substitution
R
1
R
2
1. Propyl Dialkyl Amino Substitution (10-(3-Dimethyl aminopropyl) phenothiazine
A. Promazine (Sparine®) —(CH
2
)
3
-N-(CH
3
)
2
H
B. Chlorpromazine (Thorazine®) “ “ Cl
C. Triflupromazine (Vesptin®) “ “ CF
3
2. Piperidyl ring substitution
A. Thioridazine (Mellaril®)
CH
3
—CH —CH
22
N
—SCH
3
B. Mesoridazine (Serentil®)
CH
3
—CH —CH
22
N
O
SCH
3
3. Piperazine ring substitution
A. Prochlorperazine (Compazine®)
N N
— (CH )
23
CH
3
Cl
B. Trifluoperazine (Stelazine®) “ CF
3
C. Perphenazine (Trilaphone®)
N N
— (CH )
23
CH — CH — OH
22
Cl
D. Flujenazine fenazine (Permatil®)
N N
—(CH )
23
CH — CH — OH
22
CF
3
Fig. 10.2
2. Pehnothiazine ring modification system
A. Thiothixene (Navane
®
)
C
S
H—C—CH —CH —N
22
SO — N
2
CH
3
CH
3
N—CH
3
B. Chlorprothixine (Clothixene
®
)
C
S
H—C—CH —CH —N
22
CH
3
CH
3
Cl
154 A Textbook of Medicinal Chemistry
C
S
H—C—CH —CH —N
22
X
N — CH — CH OH
22
D. Dibenzoxazine (Loxapine
®
)
N
O
Cl
C
N
N
CH
3
E. Dibenzodiazepine Clozapine (Clozaril
®
)
N
H
N
N
Cl
CH
3
Fig. 10.3
(3) Butyrophenones Derivates
O
R
F
Fig. 10.4: Basic nucleus of butyrophenone.
Derivatives Substitution R
(i) Haloperidol (Haldol
®
)
OH
Cl
N
C. Chlopenthixole X = Cl
Flupentixol X = CF
3