Aripiprazole's Receptor Interaction Profile
Aripiprazole primarily acts as a partial agonist at dopamine D2 and D3 receptors, a partial agonist at serotonin 5-HT1A receptors, and an antagonist at 5-HT2A receptors, with additional moderate affinity for several other receptors. 1
Primary Receptor Interactions
Aripiprazole exhibits high binding affinity for:
Dopamine receptors:
- D2 receptors (Ki = 0.34 nM) - partial agonist activity
- D3 receptors (Ki = 0.8 nM) - partial agonist activity
Serotonin receptors:
- 5-HT1A receptors (Ki = 1.7 nM) - partial agonist activity
- 5-HT2A receptors (Ki = 3.4 nM) - antagonist activity
Secondary Receptor Interactions
Aripiprazole shows moderate affinity for:
- Dopamine D4 receptors (Ki = 44 nM)
- Serotonin 5-HT2C receptors (Ki = 15 nM)
- Serotonin 5-HT7 receptors (Ki = 39 nM)
- Alpha-1 adrenergic receptors (Ki = 57 nM)
- Histamine H1 receptors (Ki = 61 nM)
- Serotonin reuptake site (Ki = 98 nM)
Receptors with No Significant Interaction
Aripiprazole has no appreciable affinity for:
- Cholinergic muscarinic receptors (IC50 > 1000 nM) 1
Clinical Significance of Receptor Profile
The unique receptor binding profile of aripiprazole contributes to its clinical effects and side effect profile:
Partial D2 agonism: Unlike traditional antipsychotics that are D2 antagonists, aripiprazole's partial agonist activity at D2 receptors allows it to act as a functional antagonist in dopamine-rich environments and as a functional agonist in dopamine-deficient environments 2
5-HT1A partial agonism and 5-HT2A antagonism: This combination may contribute to improvements in negative symptoms and reduced extrapyramidal side effects 3
Low H1 and muscarinic receptor affinity: Results in minimal sedation and anticholinergic side effects compared to other antipsychotics 4
PET Study Findings on Receptor Occupancy
A triple tracer PET study in patients with schizophrenia showed:
- Very high occupancy at striatal D2 receptors (87-93%)
- Moderate occupancy at 5-HT2A receptors (54-60%)
- Low occupancy at 5-HT1A receptors (16%) 3
This unique occupancy profile distinguishes aripiprazole from other antipsychotics and may explain its favorable side effect profile despite high D2 receptor occupancy.
Metabolite Activity
Aripiprazole's major metabolite, dehydro-aripiprazole:
- Has similar affinity for D2 receptors as the parent compound
- Represents approximately 40% of parent drug exposure in plasma
- Has a longer elimination half-life (94 hours vs. 75 hours for aripiprazole) 1
The combination of aripiprazole's unique receptor profile and its active metabolite contributes to its overall clinical efficacy and tolerability in various psychiatric conditions.