Biological Receptors Targeted by Rexulti (Brexpiprazole)
Brexpiprazole acts as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at serotonin 5-HT2A and noradrenergic α1B and α2C receptors. 1
Primary Receptor Targets
Brexpiprazole demonstrates high-affinity binding (expressed as Ki values) across multiple monoaminergic receptors 1:
Partial Agonist Activity
- Serotonin 5-HT1A receptors (Ki = 0.12 nM) 1
- Dopamine D2 receptors (Ki = 0.30 nM) 1
- Dopamine D3 receptors (Ki = 1.1 nM) 1
Antagonist Activity
- Serotonin 5-HT2A receptors (Ki = 0.47 nM) 1
- Serotonin 5-HT2B receptors (Ki = 1.9 nM) 1
- Serotonin 5-HT7 receptors (Ki = 3.7 nM) 1
- Noradrenergic α1A receptors (Ki = 3.8 nM) 1
- Noradrenergic α1B receptors (Ki = 0.17 nM) 1
- Noradrenergic α1D receptors (Ki = 2.6 nM) 1
- Noradrenergic α2C receptors (Ki = 0.59 nM) 1
Additional Receptor Interactions
Brexpiprazole also exhibits affinity for 1:
- Histamine H1 receptors (Ki = 19 nM)
- Muscarinic M1 receptors (67% inhibition at 10 μM)
Distinguishing Pharmacological Features
Compared to aripiprazole, brexpiprazole displays less intrinsic activity at D2 receptors and greater potency at 5-HT1A receptors. 2, 3 This unique receptor profile, where actions at 5-HT1A, 5-HT2A, and noradrenaline α1B receptors are at least as potent as its action at D2 receptors, predicts a lower propensity for activating adverse events and extrapyramidal symptoms compared to aripiprazole 4.
The balanced serotonin-dopamine activity modulation through partial agonism at both 5-HT1A and D2 receptors with similar potency, combined with potent 5-HT2A antagonism, distinguishes brexpiprazole's mechanism from other atypical antipsychotics 3. This receptor profile contributes to relatively low incidences of akathisia, insomnia, and agitation that have been commonly reported with aripiprazole 5.