Antipsychotics are drugs used to treat psychoses, which is a disorder associate with loosely organized thoughts, bizarre and illogical behaviors, hallucinations (usually auditory) and delusions. Schizophrenia is associated with these characteristics (positive symptoms).

Psychoses can be organic and related to drugs such as central anticholinergic agents, NMDA antagonist (PCP, phenyclidine) and dementia. Idiopathic psychoses possibly caused by stress.

Drugs are used in psychotic patients to produce a calming effect thus some are classified as major tranquilizers. The ones the lessen response to emotional stimuli without altering consciousness are called neuroleptics.

Typical antipsychotic blocks the dopamine at mesolimbic D2 and D3 receptors.

Atypical antipsychotic blocks the dopamine at mesolimbic D2 and D3 receptors in addition 5-HT2A

Antipsychotics

Amphetamine and lysergic acid diethylamide (LSD) used in animal models to produce schizophrenia.

Central anticholinergic produce schizophrenia by blocking M1 or M3.

Phenyclidine (PCP) induce psychosis a CNS stimulation (Dissociative Agents)

Drugs that cause schizophrenia

Treatment for psychosis

Phenothiazine

SAR Substitution at the 2-position with electron withdrawing groups increase activity alone with unshared electron pair.

Substitution at the 3-position can increase activity in comparison with unsubstituted but lesser of effect than substitution at 2-position.

Three-carbon atom chain is essential for activity. Shortening or lengthening will decrease activity (pseudo ring formation).Branching -position by methyl activity varies. Dextro isomers are more activity of chiral isomers. Alkyl groups larger than methyl cause a decrease activity.

N

S

12

34567

8 9 10

N

Cl

Dimethyl amino require for optimal activity. The monomethyl amino has less activity. Activity can be enhanced by fusion the dimethyl groups to form a piperidinepiperazines groups

The substitutes are believed to for a pseudo ring with the protonated amino group (X-ray crystal structure). Align the p-hydroxyl of Dopamine with sulfur and aliphatic amine portions. Substitution at 1-position is believe interfere with the pseudo ring formation thus a decrease in activity.

SAR continued

Important Notes for Antipsychotics

Side effects associated with antipsychotics

Extrapyramidal Side Effects (EPS): dystonia, motor restlessness Parkinson-like (rigidity and tremor), tardive dyskinesia (irreversible); alone with tachycardia, hypotension, hyperprolactinemia, gynecomastia.

Atypical antipsychotics have less risk of producing EPS

Atypical antipsychotics are effective in treating negative symptoms(social withdraw, apathy, speech deficit)Both cause increase risk of weight gain and diabetes but more so withatypical psychotics

Metabolism:Major metabolism is hydroxylation aromatic ring para to 10-nitrogen (not ring bearing EW) follow by conjugation with glucuronic acid.

Dialkylamino

Sparine (Promazine) It was introduce after 2-chloro substituted Thorazine. It is less activity than Thorazine.

Thorazine (Chlorpromazine) It was the first phenothiazine used as antipsychotic.Uses include nausea and vomiting and hiccough alone psychoses. It has significant sedative and hypotensive properties. Contraindication with antidepressant and anesthetics as with other antipsychotics.

N

S

12

34567

8 9 10

N

N

S

12

34567

8 9 10

N

Cl

Vesprin (Triflupromazine hydrochloride)Greater activity per mg in comparison with Thorazine. Lower sedative and hypotensive side effects than Thorazine

N

S

12

34567

8 9 10

N

CF3

Piperidine subgroup

Mellaril (Thioridazine hydrochloride) High anticholinergic activity.Sedation and hypotension are its side effects.Pigmentary retinopathy

Serentil (Mesoridazine Besylate)Metabolite of MellarilDoes not cause pigmentary retinopathy.

N

S

SCH3

N

N

S

123

4567

8 9 10S

N

CH3

O

C6H5SO3H

Piperazine

Compazine (Prochlorperazine maleate) More activity per mg in comparison with Thorazine. Mainly use as antiemetic.

Trilafon (Perphenazine)Use as antipsychotic and antiemetic. Ester (decanoate)IM Depot

N

S

12

34567

8 9 10

NN

Cl

2C4H4O4

N

S

NN

Cl

OH

Stelazine (Trifluperazine) Tindal (Acetophenazine)Ester (IM Depot)

Torecan (Triethylperazine)

N

S

NN

CH3

CF3 N

S

NN

COCH3

OH

N

S

NN

CH3

SCH2CH3

Prolixin (Fluphenazine HCl) Most potent on the mg basisEster (IM Depot)

Thioxanthene

Navane (Thiothixene)Replacement of the nitrogen with a double bonded carbon.Z isomers is the most active.Modified Ethyl alcohol ester (Decanoate) (Flupenthixol)

N

S

123

4567

8 9 10

NN

CF3

OH

C

S

12

34567

8 9 10S

HN

N

N

O

O

Fluorobutyrophenones

SARAR1 is a aromatic system (p-fluoro increase activity)X is carbonyl (highest activity) CHOH and CH aryl (good activity)When n=3 (highest activity) longer or shorter chain decrease activityPiperidine ring (highest activity) AR2 is required attached at 4-position.Y group as hydroxyl can improve activity.Neurotoxic metabolite (pyridine quaternary salt form)Student tried to make meperidine

meperidine

AR1 X(CH2)n NAR2

Y

N

CH3

C2H5OOC

Toxicity of Haldol

N

HO

R

Cl

R = (CH2)3 CO

F

NR

Cl

NR

Cl

+ NR

Cl

+HP HPTP

HPP +

NCH3

MAO-B

NCH3

+ NCH3

+

MPTP MPDP + MPP +

Haldol (Haloperidol)Use as antipsychotic in the treatment schizophrenia, psychoses caused by brain damage and Tourette’s syndrome.

Inapsine (Droperidol) Antipsychotic with antiemetic properitiesUsed in combination Fentanyl preanesthetic (Innovar)

F

O

N

HO

Cl

F

O

N

N

NH

O

Risperdal (Risperidone)Atypical antipsychotic Hydroxyl active metabolite (*)Antipsychotic/antidepressant (Trazodone)Structure likeCombination with Haldol for Parkinson5HT2A and D2 antagonist

Invega (Paliperidone)Approved Dec. 2006Atypical antipsychotic

N

ON

F

N

N

O

*

N

ON

F

N

N

O

OH

Daxopin (Loxapine succinate)DibenzoxazepineSide effects similar to phenothiazines.

Clozaril (Clozapine) DibenzodiazepineNot potent antipsychotic on mg basisAgranulocytosis (clinical monitoringWeekly for 6 months)

**Atypical psychotics**

67

8 9N

C

O

N

N

Cl

CH2COOH

CH2COOH NC

HN

N

N

Cl

Zyprexa (Olanzapine)Atypical antipsychoticThienobenzodiazepineD2 and strongly 5HT2

receptor antagonist

Loxitane (Loxapine)Typical antipsychoticUndergoes N-dealkylationto an active metaboliteUse often as anti-depressant

NC

HN

N

N

S CH3

NC

O

N

N

Cl

Seroquel (Quetiapine)DibenzothiazepineBinds to H1 and a1 and a2; 5-HT2A Receptors and low affinity D2 receptors

Asendin (Amoxapine)

Use often as anti-depressant

67

8 9N

C

O

N

NH

Cl

NC

S

N

NO

OH

Reglan (Metoclopramide)D2 receptor antagonistAntiemetic (chemoreceptortrigger in brain stem)Prokinetic (GI emptying)

Roxiam(S-Remoxipride)BenzamideLess EPS than Haldol

Benzamide

NH

O

N

CH3O OCH3

Br

NH

O

CH3O

Cl

NH2

N(C2H5)2