MEDICINAL CHEMISTRY-IIIMEDICINAL CHEMISTRY-III

Lecture 10 Wed. 15/ 6/ 1432H

Antipsychotic AgentsAntipsychotic Agents(Neuroleptic Agents)

(Tranquilizing Agents)

Antipsychotic agents, also called major tranquillizersAntipsychotic agents, also called major tranquillizers neuroleptics and ataractics.neuroleptics and ataractics. Antipsychotic agents produce calm or neurosedation in severely Antipsychotic agents produce calm or neurosedation in severely

disturbed psychiatric patients.disturbed psychiatric patients. They ameliorate mental aberrations that are characteristic of They ameliorate mental aberrations that are characteristic of

psychosis.psychosis. Contrary to the effect caused by hypnotics and sedatives, they Contrary to the effect caused by hypnotics and sedatives, they

don't cloud consciousness or depress the vital centres.don't cloud consciousness or depress the vital centres. They are widely used for prolonged treatment of acute and chronic They are widely used for prolonged treatment of acute and chronic

schizophrenia.schizophrenia. They antagonizing the actions of dopamine, and this is responsible They antagonizing the actions of dopamine, and this is responsible

for most of their effects on the nervous system.for most of their effects on the nervous system. Most of these agents have also antiemetic and sympatholytic Most of these agents have also antiemetic and sympatholytic

actions actions

The most important types of psychosis are:

i. Schizophreniaii. Affective disorders (e.g. depression mania)iii. Organic psychoses (mental disturbances caused by

head injury or alcoholism ……..

The main clinical features of the disease are as follows:

i. Delusions (often paranoid in nature)ii. Hallucinations, usually in the form of voices.iii. Thought disordersiv. Withdrawal from social contacts and flattening of

emotional responses.

Psychosis differ from mild behaviour Psychosis differ from mild behaviour disorders ( as anxiety ) in that …disorders ( as anxiety ) in that …

Classification

1. Rauwolfia alkaloids and synthetic analogues2. Phenothiazine and thioxanthene derivatives3. Butyrophenones4. Diphenylmethane derivatives5. Diphenylbutylpiperidines6. Miscellaneous (benzamide derivatives and tricyclic

heterocyclic analogues)

Main chemical categories are:

A. Typical neuroleptics Phenothiazines (e.g. chlorpromazine) Butyrophenones (e.g. haloperidol) Thioxanthene (e.g. flupenthioxol)B. Atypical neuroleptics benzamides (e.g. sulpiride) Diphenylbutylpiperazines (e.g. pimozide) Dibenzyldiazepines (e.g. clozapine).

2.A Phenothiazines derivatives

• (1) Propyl dialkylamino side chain(1) Propyl dialkylamino side chain• (2) Propyl piperazine side chain(2) Propyl piperazine side chain• (3) Alkyl piperidyl side chain(3) Alkyl piperidyl side chain

2.B Thioxanthene Derivatives

PhenothiazinesPhenothiazines

Chlorpromazine Hydrochloride ( Thorazine )Chlorpromazine Hydrochloride ( Thorazine )

2-chloro-10-[3-(dimethylamino)propyl] phenothiazine2-chloro-10-[3-(dimethylamino)propyl] phenothiazine

N

S

CH2CH2CH2N(CH3)2

1

2

3

46 5

7

8

9 10 Cl

HCl

•Propyl dialkylamino side chainPropyl dialkylamino side chain

synthesis

Promazine Hydrochloride Promazine Hydrochloride

10-[3-(dimethylamino)propyl]phenothiazine monohydrochloride 10-[3-(dimethylamino)propyl]phenothiazine monohydrochloride

N

S

CH2CH2CH2N(CH3)2

HCl

1

2

3

46 5

7

8

9 10

PhenothiazinesPhenothiazines•Propyl dialkylamino side chainPropyl dialkylamino side chain

PhenothiazinesPhenothiazines

Prochlorperazine maleateProchlorperazine maleate

N

S

CH2CH2CH2N1

2

3

46 5

7

8

9 10

N CH3

Cl

1

2 3

4

1 2 3

2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]phenothiazine

Propyl piperazine side chainPropyl piperazine side chain

PhenothiazinesPhenothiazines

Propyl piperazine side chainPropyl piperazine side chain Trifluoperazine. HCl ( Stelazine)Trifluoperazine. HCl ( Stelazine)

N

S

CH2CH2CH2N N CH3

CF3

10-[3-(4-methyl-1-piprazinyl)propyl]-2-(trifluromethyl)phenothiazine 10-[3-(4-methyl-1-piprazinyl)propyl]-2-(trifluromethyl)phenothiazine

N

S

CH2CH2

SCH3

NH3C

10-[2-(1-methyl-2-piperidyl)ethyl]-10-[2-(1-methyl-2-piperidyl)ethyl]-2-(methylthio)2-(methylthio)phenothiazine phenothiazine monohydrochloride.monohydrochloride.

PhenothiazinesPhenothiazines

Alkyl piperidyl side chainAlkyl piperidyl side chain

- - Thioridazine .HCl (Melleril )Thioridazine .HCl (Melleril )

Thioxanthene Derivatives

S

CH2CH2CH2

SO2N(CH3)2

N N-CH3

2-N,N-dimethyl-9-[3-(4-methyl-1-piprazinyl)propylene]thioxanthene- 2-2-N,N-dimethyl-9-[3-(4-methyl-1-piprazinyl)propylene]thioxanthene- 2-sulfonamide . sulfonamide .

Thiothixene (Navane)

• Thioxanthenes derived by isosteric replacement of one atom in the structure of phenothiazine . The compounds possess may clinical useful pharmacologic properties in common with phenothiazines.

• They are indicated for the management of the manifestation of acute and chronic schizophrenia.

AntipsychoticsAntipsychotics Phenothiazines derivativesPhenothiazines derivatives

Structure-Activity RelationshipStructure-Activity Relationship

The neuroleptic activity of phenothiazines may be affected by The neuroleptic activity of phenothiazines may be affected by the following:the following:

a.a. Nature of the chain in position 10Nature of the chain in position 10b.b. The amino groupThe amino groupc.c. 2-substituent 2-substituent

• Replacement of H in position 2Replacement of H in position 2• Substitution at position 3Substitution at position 3• Substitution at position 1Substitution at position 1• Three carbon chain…Three carbon chain…• Branching with larger groups..Branching with larger groups..• Replacement of terminal alkyl amino groupReplacement of terminal alkyl amino group

Structure-Activity Relationship• (a) Alkyl Side Chain(i) Maximum potency for antipsychotic activity when the nitrogen of the

phenothiazine ring and the more basic side chain nitrogen is connected by a THREE-CARBONS side chain.

(ii) Branching at the β-position of the side chain with a small methyl group / produces decreasing activity. This is perhaps due to……..

(iii) β-substitution with larger group causes loss of activity.(iv) Bridging of position 3 of the side chain to position 1 the phenothiazine

significantly reduces neuroleptic activity.

• (b) Basic Amino Group

(i) Maximum neuroleptic potency is observed in aminoalkylated phenothiazines having a tertiary amino group.

(ii) In general, alkylation of the basic amino group with groups larger than methyl decreases the neuroleptic potency. The diethylamine analogue is less potent than chlorpromazine.

(iii) the piperidinyl derivatives are less potent than the corresponding dimethylamine derivatives.

(iv) The substitution of position 4 of the piperazinyl or piperidinyl propyl substituted phenothiazines has been varied. Hydroxy ethyl substitution enhances potency and the acetoxyethyl derivative is even more potent. The activity decreases from N-methyl to N-propyl substitution.

(v) Quaternization of the terminal nitrogen result inn loss of activity due to inability of these polar compounds to cross the BBB.

• (c) Phenothiazine Ring Substituent (2-position)(i) Potency increase in the following order of position of ring substitution :

1 < 4 < 3 < 2.(ii) 2- substitution of the phenothiazine nucleus increases in neuroleptic

potency in the following order: OH < H < CH3 < nC3H7CO < C2H5CO < CH3CO < Cl < SCH3 < CF3.

(iii) Oxidation of the 5 sulphur of antipsychotic phenothiazine decreases activity.(iv) 1, 2, 3, 4-Aza-phenothiazine are more effective agents. The 1-Aza analogue

of promazine is more potent than the parent compound.

1-Azaphenothiazine (Prothiopendyl)