What biological receptors does Lumateperone target?

Biological Receptors Targeted by Lumateperone

Lumateperone exhibits high binding affinity for serotonin 5-HT2A receptors (Ki = 0.54 nM), moderate affinity for dopamine D2 receptors (Ki = 32 nM), and moderate affinity for serotonin transporters (Ki = 33 nM), with additional moderate binding to dopamine D1 and D4 receptors and adrenergic alpha1A and alpha1B receptors. 1

Primary Receptor Targets

High-Affinity Binding

• Serotonin 5-HT2A receptors: Lumateperone demonstrates the highest binding affinity at Ki = 0.54 nM, functioning as an antagonist at these central receptors 1
• This high 5-HT2A affinity is a key component of lumateperone's mechanism of action and contributes to its efficacy in treating schizophrenia and bipolar depression 1, 2

Moderate-Affinity Binding

• Dopamine D2 receptors: Moderate binding affinity at Ki = 32 nM, with postsynaptic antagonist activity 1

• Lumateperone acts as a presynaptic D2 agonist while functioning as a postsynaptic D2 antagonist, which contributes to its favorable side-effect profile 2

• Peak dorsal striatal D2 receptor occupancy reaches only 39% at the therapeutic 60 mg dose, occurring 1 hour post-dose 3

• Serotonin transporter (SERT): Moderate binding affinity at Ki = 33 nM 1

• Dopamine D1 receptors: Moderate affinity at Ki = 41 nM 1

• D1 receptor activity is essential for lumateperone's facilitation of NMDA and AMPA receptor-mediated currents in the medial prefrontal cortex 4

• Dopamine D4 receptors: Moderate binding affinity projected at Ki < 100 nM 1

• Adrenergic alpha1A and alpha1B receptors: Moderate binding affinity projected at Ki < 100 nM 1

Low-Affinity or Minimal Binding

• Muscarinic receptors: Low binding affinity with less than 50% inhibition at 100 nM 1

• This low muscarinic affinity reduces anticholinergic side effects such as dry mouth, constipation, and cognitive impairment 1

• Histaminergic receptors: Low binding affinity with less than 50% inhibition at 100 nM 1, 2

• The low H1 receptor affinity minimizes sedation and weight gain compared to other antipsychotics 2

• Serotonin 5-HT2C receptors: Low affinity 2

• This contributes to reduced metabolic side effects including weight gain and glucose dysregulation 2

Neurotransmitter System Modulation

Glutamatergic Effects

• Lumateperone facilitates NMDA receptor-mediated currents in the medial prefrontal cortex through a dopamine D1 receptor-dependent mechanism 4
• It also facilitates AMPA receptor-mediated currents in the prefrontal cortex 4
• Lumateperone significantly increases glutamate release in the rat medial prefrontal cortex 4

Dopaminergic Effects

• Lumateperone significantly increases dopamine release in the rat medial prefrontal cortex 4
• The simultaneous modulation of serotonin, dopamine, and glutamate neurotransmission represents lumateperone's unique multi-target mechanism 5, 2

Clinical Implications of Receptor Profile

• The low D2 receptor occupancy (39% at therapeutic doses) is substantially lower than most antipsychotics at their efficacious doses, contributing to reduced risk for extrapyramidal symptoms and hyperprolactinemia 3
• The combination of high 5-HT2A antagonism with moderate D2 antagonism allows efficacy against both positive and negative symptoms of schizophrenia while maintaining a favorable safety profile 6, 2
• The minimal binding to histaminergic and muscarinic receptors reduces common antipsychotic side effects including sedation, weight gain, and anticholinergic effects 1, 2