Download Mechanisms of Therapeutic Actions and Adverse Side Effects

Receptor Binding Profiles of Atypical Antipsychotics:
Mechanisms of Therapeutic Actions and Adverse Side Effects
5H
Mechanisms of Therapeutic Actions and Adverse Side Effects
T1A
H
1
T1
All antipsychotics (both conventional and atypical) bind to some degree at dopamine D2 receptors. It is believed that D2 antagonism mediates antipsychotics’ ability to reduce positive symptoms
of schizophrenia, including hallucinations and delusions. What sets the atypical antipsychotics apart from conventionals is the propensity of atypicals to bind additional receptors in antagonistic
or agonistic manners. Binding to additional dopaminergic, serotonergic, adrenergic, and cholinergic receptors has additional consequences, such as lessening some of the symptoms of
schizophrenia or mitigating side effects caused by D2 antagonism. For example, in addition to D2 antagonism, most atypical antipsychotics also act in an antagonistic fashion at serotonin 5HT2A
receptors. This 5HT2A antagonism is theorized to reduce the extrapyramidal symptoms (EPS) and hyperprolactinemia caused by chronic D2 antagonism.
1
D
2A
aripiprazole
2C
The vast molecular polypharmacy of atypical antipsychotics is associated not only with additional therapeutic benefits; binding to some receptor types increases a drug’s propensity to cause
adverse side effects. Chronic D2 antagonism is linked with EPS, tardive dyskinesia, and hyerprolactinemia, which are common side effects associated with conventional antipsychotics. Although
additional binding properties of atypical antipsychotics lower the risk of some D2 antagonism-associated side effects, the more complex binding profiles of atypical antipsychotics can lead to
other serious side effects. Most notably, the binding of atypical antipsychotics to 5HT2C, M3, and/or H1 receptors has been linked with cardiometabolic effects that can greatly compromise a
patient’s physical well-being
D2
5HT7
D3
T1A
5H
5HT2A
5H
H
1
1
T1
B/D
2A
2B
5HT2B
asenapine
2C
5HT2C
D1
A
5HT2A
5H
5HT2B
D1
5HT2A
1
Each atypical antipsychotic agent has a binding profile that differs from other antipsychotics. An antipsychotic’s binding profile is a summation of the receptors to which it binds, the strength
of the binding to individual receptor types (binding affinity or Ki), and the action of the drug on that receptor type (antagonism, partial agonism, etc.). The unique binding profile lends each
antipsychotic both efficacy in reducing symptoms and propensity to cause particular side effects. Two different antipsychotics may have similar adverse effects associated with them due to
having similar binding properties for certain receptor types. Conversely, one antipsychotic may be more effective at reducing affective symptoms than another due to its ability to bind a particular
receptor type with adequate affinity.
paliperidone
5HT7
D2
D3
2C
D2
B
5H
1
iloperidone
D2
T1A
5H
lurasidone
5HT7
D2
D4
Therapeutic
Effects
D2 Antag
D2 PA
+++
D3
+++
+++
+
++
?
++
+++
+
+++
+++
+++
+
+++
+++
++
+++
+
+++
+++
Reduced positive
symptoms
Reduced positive
symptoms
Reduced positive
symptoms;
Reduced negative
symptoms;
Procognitive;
Antidepressant
Unknown
EPS;
Relatively lower
Hyperprolactinemia; risk of EPS
Increased negative
symptoms;
Side Effects Increased negative
symptoms;
Increased cognitive
deficits; Sedation
+ weak binding affinity (100>Ki<1000)
++ moderate binding affinity (10>Ki<100)
+++ strong binding affinity (1>Ki<10)
++++ very strong binding affinity (Ki<1)
? No data yet available
* Binding property due primarily to the metabolite norquetiapine
5HT1A
+++
++
+
++
+++
+
+*
+
++
5HT2A
++
++++
++
+++
++
+++
++++
++*
++++
++++
5HT2C
++
++++
++
+
+
++
++
+*
++
++
Reduced EPS;
Reduced EPS;
Antidepressant
Reduced
Reduced
hyperprolactinemia; hyperprolactinemia
Antidepressant;
Anxiolytic
Unknown
Cardiometabolic
Cardiometabolic
5HT7
+++
++++
++
++
++++
+
+++
++*
+++
+++
α1
++
+++
+++
+++
++
++
+++
+++
+++
++
Reduced
Reduced
circadian rhythm nightmares
dysfunction;
Reduced negative
symptoms;
Procognitive
Unknown
Dizziness;
Sedation;
Hypotension
M1
+
+++
M3
++
H1
++
+++
+++
++
1
2B
quetiapine
5HT2C
2C
NET
1E
5HT
D1
D2
D3
X
++
++*
Reduced EPS
++
++*
Reduced EPS
+++
++
+++*
++
++
5HT2A
1
risperidone
2C
Hypnotic
D4
D3
D2
5HT2A
Constipation;
Sedation; Dry
mouth; Blurred
vision
Cardiometabolic;
Constipation;
Sedation; Dry
mouth; Blurred
vision
Cardiometabolic;
Sedation
5H
T1
B/D
ziprasidone
5HT7
5HT7
T6
5H
D2
Drug
Aripiprazole
Asenapine
Clozapine
Iloperidone
Lurasidone
Olanzapine
Paliperidone
Quetiapine
Risperidone
Ziprasidone
T6
D1
5HT2A
5HT2A
1
D
5H
1E
D3
M4
H
1
5HT2B
5HT7
2C
5HT
D4
M3
2A
2B
clozapine
3
M2
T1
2A
T
5H
M1
X
5HT2A
1
5HT2C
D4
D2
D3
X
H
1
5HT2B
2C
5HT2C
M4
T1
1
olanzapine
T1A
M3
D4
D3
M4
1
5H
M2
T1
5H
X
M1
5HT7
5H
5H
T6
T5
M3
H
1
5HT7
5HT2B
M2
5HT2A
T6
5H
M1
5H
5HT2A
X
D3
D2
Correll CU. Eur Psychiatry 2010;25(Suppl 2):S12-21.
Nasrallah HA. Mol Psychiatry 2008;13(1):27-35.
National Institutes of Mental Health Psychoactive Drug Screening Program. Cited 2012 Aug.
Available from: http://pdsp.med.unc.edu/indexR.html.
Stahl SM. Stahl’s essential psychopharmacology. 3rd ed. New York, NY: Cambridge University
Press; 2008
Presented at the 2012 NEI Global Psychopharmacology Congress.
This poster is supported by an unrestricted educational grant from Sunovion Pharmaceuticals Inc.