PHAR 752 Wilson + Gisvold, Ch. 14, pp. 496-503.

Antipsychotic Agents (Medicinal Chemistry)

Six classes of antipsychotics Phenothiazines Propyl dialkylamino side chain Chlorpromazine (Thorazine) Propyl piperazine side chain Fluphenazine (Prolixin or Prolixin Enanthoate or Prolixin Decanoate) Alkyl piperidyl side chain Thioridazine HCl (Mellaril) Thioxanthenes Thiothixene HCl (Navane) Dibenzazepines Dibenzodiazepine Clozapine (Clozaril) Olanzepine (Zyprexa) Dibenzooxazepine Loxapine (Loxitane) Dibenzothiazepine Quetiapine (Seroquel) Fluorobutyrophenones Haloperidol (Haldol or Haldol decanoate) Droperidol (component of Innovar) Diphenylbutylpiperidines Pimozide (Orap) Miscellaneous heterocyclic compounds Risperidone (Risperdal) Ziprasidone (Geodon) Aripiprazole (Abilify) Phenothiazines - SAR
7 4

1) Position 2 is the best position for substitution. Activity generally increases with the electron-withdrawing ability of the substituent. 2 2) Substitution at positions 1 and 4 both decrease antipsychotic N R 1 activity (position 1 > position 4). Unsubstituted phenothiazines have 10 1 weak antipsychotic activity. 3) Three carbon chain connecting nitrogens is required. Two or four " carbon chain greatly decreases activity. 4) Branching on the sidechain with large groups decreases activity. R ! Branching at the ! carbon (as is seen in alkyl piperidyl side chains) is N tolerated. 5) Basic nitrogen substituents Tertiary amines provide optimal R activity; secondary amines have decreased activity. Significant increases in size from the dimethylamino group (see chlorpromazine) decrease activity. Piperidine (see thioridazine) and piperazine rings (fluphenazine) are allowed. Addition of chain length on the N2 of the piperazine ring is proposed to increase receptor binding forces.
3

The tertiary amine is required for passage thru BBB, but the protonated ammonium species is the important form at the receptor.

Evolution of the Phenothiazine Antipsychotics

O N CH3

CH3 N O CH3

CH3

Ethanolamines (antihistamine activity)

Diphenhydramine (antihistamine)

CH3 CH3 N N CH3 N N N CH3

Ethylenediamines (antihistamine activity)

Tripelennamine (antihistamine)

CH3 N N S CH3 S N

CH3 N CH3 CH3

Diethazine (anti-Parkinson)

Promethazine (antihistamine)
Cl

N S

CH3

CH3

Chlorpromazine (antipsychotic)

Antipsychotics - Phenothiazines
Propyl dialkylamino sidechain
S N Cl

Chlorpromazine (Thorazine)

CH3

CH3

Propyl piperazine sidechain

S N CF3

N N

Fluphenazine HCl (Permitil) Fluphenazine decanoate (Prolixin) Primary hydroxyl is site of esterification to form lipophilic decanoate ester which is used for depot injections.

OH

Metabolism of Chlorpromazine
Over 100 metabolites of chlorpromazine have been identified. Examples below demonstrate major routes.
O S N Cl

CPZ sulfoxide (inactive)

CH3

CH3

Cyp3A4
S N Cl

Cyp2D6

S N Cl

CH3

CH3

N H

CH3

Chlorpromazine (CPZ) Cyp2D6 (major) Cyp1A2 (minor)

HO S N Cl

Nor1-CPZ (weakly active)

S N Cl

CH3

CO2H

CH3

CPZ propionic acid (inactive) Glucuronidation and excretion

7-Hydroxy CPZ (weakly active)

Alkyl piperidyl sidechain

S N SCH3

CH3

Thioridazine (Mellaril) R enantiomer has higher affinity for D2 receptor

S SO2N(CH3)2

Thioxanthenes

Thiothixene (Navane)

N N CH3

Nitrogen atom in phenothiazine is replaced with a carbon atom which forms a double bond with the first carbon in the sidechain. Z isomer (cis isomer) is more active than E isomer (trans) Electron-withdrawing group at position 2 is an N,N-dimethylsulfonamide in this example.

CH3 N N N Cl N H

Dibenzazepines (Dibenzodiazepines)

Clozapine (Clozaril) Atypical antipsychotic

CH3 N N N CH3

N H

Olanzapine (Zyprexa) Atypical antipsychotic

CH3 N N N Cl O

Dibenzazepines (Dibenzooxazepines)

Loxapine (Loxitane)

OH O

Dibenzazepines (Dibenzothiazepines)

N N N

Quetiapine (Seroquel) Atypical antipsychotic

Fluorobutyrophenones SAR
F X N

Y AR

1)!X = C=O (ketone) for optimal activity. X = C(H)OH or C(H)aryl also yield good activity. 2)!Altering length or branching of the three-carbon chain linking keto and amino group decreases antipsychotic activity. 3) Basic nitrogen is incorporated into a six-membered ring for optimal activity. 4) AR is an aromatic ring attached directly to or separated by one atom from position 4 of the sixmembered ring. 5) The Y group is variable and can enhance activity (Y= OH in haloperidol)

Y F O N

Fluorobutyrophenones

Haloperidol (Haldol), Y = OH
Cl

Haldol decanoate (decanoate ester of tertiary alcohol) Y=

O O C(CH2)8CH3

F N O N O NH

Fluorobutyrophenones

Droperidol (in Innovar with fentanyl)

Diphenylbutylpiperidines
F N N O NH

Pimozide (Orap)

Analogs of butyrophenones in which carbonyl is replaced by a CH-phenyl group (compare to haloperidol). Pimozide is approved for the treatment of Tourette's syndrome.

N N O

CH3 N

Miscellaneous Heterocyclic Compounds

F O

Risperidone (Risperdal) Atypical antipsychotic

OH N N O CH3 N

F O

Paliperidone (= 9-hydroxyrisperidone) Atypical antipsychotic

H N O

Cl

N N

Ziprasidone (Geodon) Atypical antipsychotic

Miscellaneous Heterocyclic Compounds

O H N O N N Cl Cl

Aripiprazole (Abilify) Atypical antipsychotic