Transcript Document

Neuroleptic Antipsychotics

Treatment of Psychoses:

Schizophrenia, Depression, Manic-Depressive Disorder Macbeth: How does your patient, doctor? Doctor: Not so sick, my lord, as she is troubled with thick-coming fantasies, that keep her from her rest.

Macbeth: Cure her of that: Canst thou not minister to a mind diseas’d; pluck from the memory a rooted sorrow; raze out the written troubles of the brain; and with some sweet oblivious antidote cleanse the stuff’d bosom of that perilous stuff which weighs upon the heart?

Doctor: Therein the patient must minister to himself.

-William Shakespeare, Macbeth Davis MDCH 5210 - Antipsychotics, 2005 1

Neuroleptic Definition

S H N Cl N Cl CH 2 CH 2 CH 2 N(CH 3 ) 2


H 3 C N N N

What is a “neuroleptic”?


Neuroleptic compounds are CNS depressants that do not generally cause a loss of consciousness by themselves. The can produce a state of “artificial hibernation” by themselves and in combination with anesthetics. This indicates that the patient can be aroused from this state, differentiating it from anesthesia.

Neuroleptics potentiate the action of anesthetics, and this action is a defining factor. These effects are usually thought due directly to activity at D 2 receptors.

Reserpine is also an antipsychotic due to its effects on dopamine levels, but it is non-selective with many side effects.

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Properties of Neuroleptic Antipsychotics.

•Modest sedative activity •Low potential for lethality •Low abuse potential, non-euphoric •Motor Inhibition •Anti-emetic due to dopamine antagonism of the chemoreceptor trigger zone (CTZ).

•Diminish conditioned responses, but not unconditioned.

Conditioned: Spontaneous movement and complex behaviors. Conditioned avoidance. Think Pavlov’s dog. The bell, but not the shock.

Unconditioned: Spinal reflexes, nociceptive avoidance behaviors remain intact. The shock.

Emotional responses are reduced.

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Antipsychotic Mechanism(s). Primarily Dopamine Antagonists.

Act at D 2 , D 3 , and D 4 receptors. D 2 agonist activity inhibits adenylate cyclase.

Chlorpromazine is the prototype drug in terms of SAR and in terms of activity profile.

Chlorpromazine has a 50:1 D also binds D 4 2 /D 3 affinity.

Clozapine (the prototype atypical antipsychotic) has a 4:1 receptor ratio. Clozapine about 10-fold better than D 2 .

Most anti-psychotics have  -adrenergic antagonist activity. Chlorpromazine is more active at adrenergic receptors than haloperidol.

Clozapine, the “atypical” antipsychotic has high affinity for 5HT 2 ,  1 , and histamine H 1 receptors. Actually better than D 1 or D 2 .

All neuroleptic antipsychotics have antimuscarinic effects as well as anti-emetic activity associated with anti-dopaminergic activity.

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Dopaminergic Neurons

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Phenothiazine SAR


1. Propyl Side Chain

N 2 X CH 2 CH 2 CH 2 NR 2 1 2 3 •Propyl is best, butyl is nearly inactive, ethyl has low activity. Compounds with ethyl chains often have antihistaminic activity.

•Any substituent at the first position of the side chain decreases activity.

•Substitution of a methyl at position 2 of the chain is OK, phenyl is OK. Large aliphatic substituents are not tolerated.

•A larger range of substitutions are tolerated at position 3. The nitrogen is often included as part of a ring.

2. Modification of X and the the Tricyclic Nucleus

•Highest activity is associated with an electron withdrawing, lipophilic substituent (halogen) at position 2. A trend in activity changes can be seen with alterations in the identity of X; increasing lipophilicity and e- withdrawing increases activity.

•Disubstitution of the ring decreases activity, ring cleavage is inactivating.

•Replacing S with C, O, Se, etc. decreases activity. Replacing the nitrogen eliminates activity (except in special cases.

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Phenothiazine SAR - Page 2 3. Modification of Side Chain Amino Group

•The highest activity is for 3 ° amines (pKa’s of 8-10). Methyl R groups on nitrogen have greater activity that larger aliphatic groups. The receptor is long and narrow as shown by the amino substitution and by the tolerance to phenyl substitution at C2.

•The amino group can be part of a cyclic structure. The cyclic amines include pyrrolidine, piperidine, and piperazine. The piperazine substituent, in particular, generally increases potency.

N 2 X CH 2 CH 2 CH 2 NR 2 1 2 3 CH 2 CH 2 CH 2 N(CH 3 ) 2 (CH 2 ) 3 N Propyl dimethylamino side chain (chlorpromazine (Thorazine)) Alkyl piperdinyl and pyrrolidinyl side chain ( thioridazine (Mellaril)) Propyl piperazine side chain ( prochlorperazine (Compazine)) (CH 2 ) 3 N (CH 2 ) 3 N N R 7 Davis MDCH 5210 - Antipsychotics, 2005

Identity of Phenothiazine X and Effects on Potency

O O O O OH < H < OCH 3 < CH 3 < CCH 3 ~ SCH 3 < Cl < SCH 3 ~ SCH 3 ~ Br ~ SCF 3 < SCF 3 < CF 3 O O The order of potency for a “few” X substitutents are shown. The most important are indicated by arrows, and Cl of course.

Phenothiazine Metabolism

Three major processes; all give compounds that are less active.

Ring hydroxylation – followed by glucuronidation N-dealkylation terminal nitrogen Oxidation at S and at terminal nitrogen.

S N 2 X CH 2 CH 2 CH 2 NR 2 1 2 3 8 Davis MDCH 5210 - Antipsychotics, 2005

Phenothiazine/Thioxanthene Neuroleptics

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Long Acting Neuroleptics Davis MDCH 5210 - Antipsychotics, 2005 10

Thioxanthene Antipsychotics.


Cis double bond compounds are much more active than trans. Double bond reduction reduces activity.

Other SAR is the same as for the phenothiazines

H S 2 X CH









Chlorprothixene (Taractan) - 1x chlorpromazine R = (CH 2 ) 2 N(CH 3 ) 2 X = Cl Thiothixene (Navane) - 10x chlorpromazine O CH 3 R = (CH 2 ) 2 N N CH 3 X = S N O CH 3 Davis MDCH 5210 - Antipsychotics, 2005 11

Three Dimensional SAR of Typical and Atypical Antipsychotics.

N CH 3 H N Cl N N N N Cl N H H 3 C N Clozapine N Clozapine N CH 3 N Cl O Loxapine O N N N CH 3 Loxapine Cl S N Cl CH 2 CH 2 CH 2 N(CH 3 ) 2 Chlorpromazine Davis MDCH 5210 - Antipsychotics, 2005 12

N CH 3 Cl N N N H Clozapine N CH 3 N N N H S CH 3 Olanzapine (Zyprexa) Atypical

The Atypical Antipsychotics

N N N CH 3 Cl O Loxapine S N Ziprasidone (Geodon) Atyical N N N O N CH 3 N N O Risperidone (Risperdal) Atypical F N N N O OH Cl N H O S Quetiapine (Seroquel) Atypical Davis MDCH 5210 - Antipsychotics, 2005 13

The History/Evolution of Butyrophenone Neuroleptics.

O OC 2 H 5 CH 3 N Meperidine O N O OC 2 H 5 Propophenone 200 x Meperidine as an Analgesic O N O OC 2 H 5 Butyrophenone Analgesia similar to Meperidine Other activity similar to Chlorpromazine F O N OH Cl Haloperidol (Haldol) Prototype butyrophenone antipsychotic 10x Chlorpromazine Davis MDCH 5210 - Antipsychotics, 2005 14

• • • • •

Butyrophenone SAR

butyro X N Y R 1 R Phen O one For highest potency, X is always F. –OCH 3 has the lowest potency. This tells you that an electron withdrawing group, not electron donating is optimal.

Shortening, lengthening, or branching of the propyl chain decreases potency Replacing the keto oxygen with S, carbon, OH decreases potency A 3 ° N is necessary, analogous to phenothiazines Y is usually C with two R groups, but may be N. For example piperazine instead of piperdine.

Examples: Haloperidol: This is the prototype for this class. One variation is to esterify the OH with decanoic acid to increase the duration.

Droperidol (Inapsine): Strong sedative. In combination with Fentanyl (an analgesic) is given as a preanesthetic sedative (Innovar). Droperidol is also antiemetic which is important.

Trifluperiodol: Similar to Haloperidol 15 Davis MDCH 5210 - Antipsychotics, 2005

Butyrophenone Neuroleptics F N O Droperidol (Inapsine) O N NH F F H O Trifluperidol N OH CF 3 N O N NH F Pimozide (Orap) "diphenylbutylpiperidine" similar to haloperidol, longer duration. Used for Tourette's Syndrome.

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N CH 3 O Cl N N N N Cl N N H CH 3 Most of the neuroleptics have anticholinergic activity. The “atypical” antipsychotics also generally have  1 adrenergic antagonist activity.

S H 3 C N Cl CH 2 CH 2 CH 2 N(CH 3 ) 2 Chlorpromazine H C O NCH 3 HN N CH 2 N Benztropine OH Phentolamine (Regitine) non-selective  antagonist Davis MDCH 5210 - Antipsychotics, 2005 17

Dopamine D4 receptors elevated in schizophrenia

PHILIP SEEMAN * , HONG-CHANG GUAN * & HUBERT H. M.VAN TOL * Nature 365, 441 - 445 (1993)

Schizophrenia: More dopamine, more D


Philip Seeman and Shitij Kapur



July 5, 2000

| vol. 97 | no. 14 |


Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine hypothesis. As originally put by Van Rossum in 1967(ref. 1 , p. 321), "When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could be part of the aetiology ...[emphasis added]." Indeed, this speculative sentence by Van Rossum foreshadows the title of the important work by Abi-Dargham et al. ( 2 ) in this issue of PNAS: "Increased baseline occupancy of D 2 receptors by dopamine in schizophrenia." Davis MDCH 5210 - Antipsychotics, 2005 18

More Dopamine Fig. 1. Method and findings of Abi-Dargham et al. (2) to reveal an increased occupancy of dopamine D 2 receptors in schizophrenia. (Top) The number of dopamine D 2 receptors, measured by the [ 123 I]IBZM binding potential (green triangles with I), were the same in the brain striata of control and schizophrenia subjects. The levels of synaptic dopamine (pink triangles with D), which is higher in patients compared to control subjects, normally occupies most of the D 2 receptors, masking the difference between control and schizophrenia individuals. (Bottom) After partial depletion of endogenous brain dopamine by oral ingestion of methylparatyrosine over 2 days, the binding of [ patients rose significantly higher.

123 I]IBZM rose in both the control and schizophrenia subjects, but that for the Davis MDCH 5210 - Antipsychotics, 2005 19

Still More Dopamine Fig. 2. Possible model to account for the increased number of dopamine D 2 receptors in schizophrenia seen with [ 11 C]methylspiperone but not with [ 11 C]raclopride. It is known that the photolabel of spiperone ([ 125 I]azidophenethylspiperone) primarily or selectively labels monomers of D 2 receptors, whereas the benzamide photolabel ([ and oligomers of D 2 the total population of D [ 11 2 schizophrenia but not with [ 125 I]azido-iodo nemonapride) unselectively labels monomers, dimers, receptors (see text). These findings suggest that even if there is no increase in receptors in schizophrenia, an increase in the proportion of monomers caused by the increased level of dopamine in schizophrenia (see Fig. 1) would result in an increase in the binding of C]methylspiperone (red triangle with S) in 11 C]raclopride (white triangle with R). Davis MDCH 5210 - Antipsychotics, 2005 20

Am J Psychiatry. 2004 Sep;161(9):1620-5 Dopamine Receptors and Clozapine

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics.

Tauscher J


Hussain T


Agid O


Verhoeff NP


Wilson AA


Houle S


Remington G


Zipursky RB


Kapur S


• •OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5 HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. •RESULTS: The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). •CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.

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Questions: Dopamine Hypothesis

What were some of the reasons that D3 and D4 receptors are attractive antipsychotic targets?

What is the status of the D3 and D4 receptors as important sites for antipsychotic action?

Do Schizophrenics have higher DA levels, or do they have a higher number of DA receptors?

How were the levels of DA and DA receptors determined in the Abi-Dargham et al. study?

What is the role of 5HT receptors in schizophrenia? Modulation of DA?

What is the status of the “Dopamine Hypothesis” according to Seeman?

Does the DA receptor binding of clozapine support the “DA hypothesis”?

What is an “atypical antipsychotic”?

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Is antipsychotic therapy counterintuitive, or do we simply not understand brain function?

FIGURE 3. (A) Proposed model of modulation of DA cell activity by cortical projections. This model, adapted from Carlsson and colleagues, 70 negative glutamate regulation is altered.

proposes a bimodal modulation of DA activity in the ventral tegmental area (VTA) by glutamatergic (GLU) projections originating in the frontal cortex. DA levels in cortex may be reduced in schizophrenic brain, increasing midbrain levels. Balance of positive and

Glutamate, Dopamine, and Schizophrenia. From Pathophysiology to Treatment MARC LARUELLE, LAWRENCE S. KEGELES and ANISSA ABI DARGHAM.

Ann. N.Y. Acad. Sci. 1003: 138-158 (2003).

Do we still believe in the dopamine hypothesis? ANISSA ABI DARGHAM. Int. J. Neuropsychoparm. (2004) 7, Supp S1-S5

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