Neuroleptic Antipsychotics

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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 diseasd pluck from the
memory a rooted sorrow raze out the written
troubles of the brain and with some sweet
oblivious antidote cleanse the stuffd bosom of
that perilous stuff which weighs upon the
heart? Doctor Therein the patient must minister
to himself. -William Shakespeare, Macbeth
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Neuroleptic Definition
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 D2 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
Pavlovs 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 D2, D3, and D4 receptors. D2 agonist
activity inhibits adenylate cyclase. Chlorpromazi
ne is the prototype drug in terms of SAR and in
terms of activity profile. Chlorpromazine has a
501 D2/D3 affinity. Clozapine (the prototype
atypical antipsychotic) has a 41 receptor ratio.
Clozapine also binds D4 about 10-fold better
than D2. Most anti-psychotics have ?-adrenergic
antagonist activity. Chlorpromazine is more
active at adrenergic receptors than
haloperidol. Clozapine, the atypical
antipsychotic has high affinity for 5HT2, ?1, and
histamine H1 receptors. Actually better than D1
or D2. 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
• 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 (pKas 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.

Propyl dimethylamino side chain (chlorpromazine
(Thorazine)) Alkyl piperdinyl and pyrrolidinyl
side chain (thioridazine (Mellaril)) Propyl
piperazine side chain (prochlorperazine
(Compazine))
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Identity of Phenothiazine X and Effects on Potency

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.
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Phenothiazine/Thioxanthene Neuroleptics
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Long Acting Neuroleptics
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Thioxanthene Antipsychotics.
SAR Cis double bond compounds are much more
active than trans. Double bond reduction reduces
activity. Other SAR is the same as for the
phenothiazines
Chlorprothixene (Taractan) - 1x chlorpromazine R
(CH2)2N(CH3)2 X Cl
Thiothixene (Navane) - 10x chlorpromazine
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Three Dimensional SAR of Typical and Atypical
Antipsychotics.
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The Atypical Antipsychotics
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The History/Evolution of Butyrophenone
Neuroleptics.
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Butyrophenone SAR

• For highest potency, X is always F. OCH3 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
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Butyrophenone Neuroleptics
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Anticholinergic activity
Most of the neuroleptics have anticholinergic
activity. The atypical antipsychotics also
generally have ?1 adrenergic antagonist activity.
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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 D2
receptors Philip Seeman and Shitij Kapur
PNAS July 5, 2000 vol. 97 no. 14 7673-7675
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 D2 receptors by dopamine in schizophrenia."
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More Dopamine
Fig. 1. Method and findings of Abi-Dargham et
al. (2) to reveal an increased occupancy of
dopamine D2 receptors in schizophrenia. (Top) The
number of dopamine D2 receptors, measured by the
123IIBZM 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 D2
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 123IIBZM rose in both the
control and schizophrenia subjects, but that for
the patients rose significantly higher.
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Still More Dopamine
Fig. 2. Possible model to account for the
increased number of dopamine D2 receptors in
schizophrenia seen with 11Cmethylspiperone but
not with 11Craclopride. It is known that the
photolabel of spiperone (125Iazidophenethylspipe
rone) primarily or selectively labels monomers of
D2 receptors, whereas the benzamide photolabel
(125Iazido-iodo-nemonapride) unselectively
labels monomers, dimers, and oligomers of D2
receptors (see text). These findings suggest that
even if there is no increase in the total
population of D2 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 11Cmethylspiperone (red triangle
with S) in schizophrenia but not with
11Craclopride (white triangle with R).
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Dopamine Receptors and Clozapine
Am J Psychiatry. 2004 Sep161(9)1620-5

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