Tranquilizers

A tranquilizer is a drug that acts on the CNS and is used to calm,

decrease anxiety, or help a person to sleep.

Often called depressants because they suppress the CNS and slow the

body down.

Used to treat mental illness that are characteristic of the psychoses

which is a behavioral disorder.

Also used in common anxiety and sleeplessness.

Can cause dependence and certain ones can easily be abused.

Minor tranquilizers are called anxiolytics and major tranquilizers are

called Antipsychotics.

Tranquilizers

Psychoses eg Schizophrenia

Affective disorders eg Depression and Mania

Major Psychiatric Disorders

False perceptions (Hallucinations)

False beliefs (Delusions)

Psychosis

Emotional disturbances: Mood is very low (Depression) Mood is very high (Mania)

Affective Disorders

Most common form of psychosis (1% of world population)

Most typical features are : -Delusions -Hallucinations -Disorganised thinking -Emotional abnormalities

Schizophrenia

Psychosis:

The psychosis are inhibition of mood and emotional responses.

Psychiatric illness can be divided into neurosis and psychosis.

Neurosis is a class of functional mental disorders involving distress but

neither delusions nor hallucinations. Neurosis may also be called

psychoneurosis or neurotic disorder.

The psychotic patient have difficulty in understanding reality and their own

conditions, they live in a world of his own.

They experience hallucinations and delusions (paranoid in nature), thought

disorders and withdrawal from social contacts and flattering of emotional

responses.

An excess in dopaminergic signaling is hypothesized to be

linked to the positive symptoms of psychosis, especially those of

schizophrenia.

Many antipsychotic drugs accordingly target the dopamine

system

I. First generation

1) Phenothiazine derivatives: Chlorpromazine HCl,

Triflupromazine, Thioridazine HCl, Mesoridazine HCl,

2) Butyrophenones: Haloperidol, Droperidol, Resoperidone.

3) Thioxanthenes: Flupenthixol, Clopenthixol, Zuclopenthixol.

II. Second generation

Aripiprazole, Clozapine, Zotepine, Olanzapine, Risperidone, etc.

Classification

ChlorpromazineHaloperidol

FluphenazinePerphenazine

Thioridazine

Prochlorperazine

Structures of some antipsychotics

I. Modification in tricyclic systems:

a) Most of the compounds have either a six membered central ring (6-6-6).

(Example : phenothiazine) classes for good antipsychotic activity.

b) Compounds having larger central ring (Eg. Imipramine 7- membered)

and smaller central ring, Eg. carbazole (5 membered ring) are lack in

antipsychotic activities and produce only antidepressant activity).

c) Analogues of tricyclic compounds that lock a central ring (Eg. Rimozide)

generally devoid of antipsychotic activity.

N

S

R10

R2

SAR for phenothiazine

b) Introduction of methyl group at position 1, 2 or 3 of 3 – amines propyl side chain decreases the antipsychotic activity and may result Imipramine like activity. c) Bridging of position 3 of side chain to position 1 of phenothiazine nucleus reduces neuroleptic activity.

SAR for Phenothiazine derivatives

N

S

R10

R2II. Modifications of alkyl side chain at R10: :

a) The maximum potency is obtained when the

nitrogen of phenothiazine and basic amino group is

connected by a three carbon side chain, because it

permits maximum resemblance with that of most

preferred conformational form of dopamine.

a) Maximum neuroleptic potency is obtained in amino alkyl substituents having 3°

amines group than 2° and 1° amines group containing compounds.

b) Alkylation of basic amino group with groups larger than methyl group decreases

neuroleptic potency. Example: Diethylamine analogues.

c) Replacement of dimethylamine group with Pyrrolidine, morpholine groups

decreases the neuroleptic potency.

d) The activity is retained or increased if the amino group is replaced with

piperidyl or Piperazine groups. Example : Mesoridazine, carphenazine.

SAR for Phenothiazine derivatives

N

S

R10

R2III. Modifications of basic amino group:

e) Bridged piperidine derivatives retains the neuroleptic

activities.

f) Introduction of hydroxyl, methyl, hydroxy-ethyl groups to

piperidine and Piperazine moieties increase the potency.

g) N4-Piperazine substituents with phenyl ethyl, p – amino

phenyl ethyl or estirified long chain fatty acids increases the

activity.

SAR for Phenothiazine derivatives

N

S

R10

R2III. Modifications of basic amino group:

a) Substituents at position 2 is optimal for neuroleptic potency.

b) 2–substitution is an electron withdrawing group increases the

neuroleptic activity, the potency increases in the following order OH <>

c) Oxidation of sulfur at 5 – position decrease the neuroleptic activity.

d) 1-Azo phenothiazine is more potent than parent compound. Example:

Prothipendyl.

SAR for Phenothiazine derivatives

N

S

R10

R2IV. Phenothiazine ring substituents at R2:

Prothipendyl

Mechanisms of action -competitive blockade of dopamine receptors and

serotonin receptors -adverse effect result from blockade of different

receptors

Antipsychotic Drugs

Synthesis of Chlorpromazine

Chlorpromazine

2-Chlorophenothiazine 3-Chloropropyl-dimethylamine

Synthesis of Prochlorperazine

Prochlorperazine

2-Chlorophenothiazine

Chlorpromazine, Fluphenazine, Thioridazine, Trifluoperazine

Similar therapeutic effects Different potency and side effect Chlo. And Thio. lower potency, more autonomic side

effects and fewer extrapyramidal side effects than high potency

Flu. Higher potency

Phenothiazines

Blockade of D2 receptors Positive symptoms of Sch. Decrease in 1-3 weeks Less agitated, fewer auditory hallucinations, disappear of

paranoid delusions Behavioural improvement

Mechanisms of therapeutic effects