Biological Receptors Targeted by Aripiprazole
Aripiprazole exhibits a unique multi-receptor binding profile, functioning primarily as a partial agonist at dopamine D2 and serotonin 5-HT1A receptors while acting as an antagonist at serotonin 5-HT2A receptors. 1
Primary Receptor Targets (High Affinity)
Aripiprazole demonstrates highest binding affinity for the following receptors:
- Dopamine D2 receptors (Ki = 0.34 nM): Acts as a partial agonist with functionally selective properties depending on cell type and pathway examined 1, 2
- Dopamine D3 receptors (Ki = 0.8 nM): Displays partial agonist activity 1, 2
- Serotonin 5-HT1A receptors (Ki = 1.7 nM): Functions as a partial agonist 1, 2
- Serotonin 5-HT2A receptors (Ki = 3.4 nM): Acts as an antagonist 1, 2
- Serotonin 5-HT2B receptors: Functions as an inverse agonist (highest affinity among all receptors tested) 2
Secondary Receptor Targets (Moderate Affinity)
Aripiprazole has moderate binding affinity (15-98 nM) for additional receptors:
- Dopamine D4 receptors (Ki = 44 nM): Partial agonist activity 1, 2
- Serotonin 5-HT2C receptors (Ki = 15 nM): Partial agonist activity 1, 2
- Serotonin 5-HT7 receptors (Ki = 39 nM) 1, 3
- Alpha1-adrenergic receptors (Ki = 57 nM) 1, 3
- Histamine H1 receptors (Ki = 61 nM) 1, 3
- Serotonin reuptake site (Ki = 98 nM) 1
Receptors with Minimal or No Affinity
Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM), which distinguishes it from many other antipsychotics and contributes to its favorable side effect profile regarding anticholinergic effects 1
Clinical Implications of Receptor Profile
The unique receptor binding pattern explains aripiprazole's classification as a "third-generation" antipsychotic, distinguishing it from typical dopamine antagonists and second-generation serotonin-dopamine antagonists 4. This profile results in:
- Lower sedation compared to antipsychotics with higher histamine H1 affinity, making it preferable when sedation is undesirable 5
- Reduced extrapyramidal symptoms despite high D2 occupancy (85-93% at therapeutic doses), likely due to partial agonist rather than pure antagonist activity 6
- Minimal anticholinergic effects due to negligible muscarinic receptor binding 1, 7
- Low propensity for weight gain, metabolic disturbances, and prolactin elevation compared to other atypical antipsychotics 7, 8
Important Caveat on D2 Receptor Activity
The functional effects of aripiprazole at D2 receptors are cell-type selective, meaning it can display agonism, partial agonism, or antagonism depending on the specific cellular context and pathway examined 2. This "functionally selective" property likely contributes to its therapeutic efficacy in treating both positive and negative symptoms while minimizing side effects 2, 8.