Blonanserin is a Potent and Orally Active 5-HT2A and Dopamine D2 Receptor Antagonist

5-HT receptors (Serotonin receptors) are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs). They mediate both excitatory and inhibitory neurotransmission. The 5-HT receptors modulate the release of many neurotransmitters, as well as many hormones. The 5-HT receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, memory,  mood, nausea, sleep. Preclinical studies show that 5-HT2AR antagonists have antipsychotic and antidepressant properties, whereas agonist ligands possess cognition-enhancing and hallucinogenic properties. Abnormal 5-HT2AR activity takes part in a number of psychiatric disorders and conditions, including depression, schizophrenia, and drug addiction.

Dopamine Receptors are also a class of GPCRs that in the vertebrate central nervous system. Dopamine receptors play an important role in many neurological processes, including motivation, pleasure, and learning. Abnormal dopamine receptor signaling and dopaminergic nerve function play an important role in several neuropsychiatric disorders. There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. Dopamine D2-autoreceptors play a key role in regulating the activity of dopamine neurons and control the synthesis, release and uptake of dopamine.

Blonanserin (AD-5423) is an orally active 5-HT2A and dopamine D2 receptor antagonist.

Blonanserin usually acts as an atypical antipsychotic agent. It has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. Blonanserin exerts some blockade of α1-adrenergic receptors and also shows significant affinity for the D3 receptor. Blonanserin possesses low affinity for the sigma receptor, but lacks significant affinity for numerous other sites including the 5-HT1A, 5-HT3, D1, α2-adrenergic, β-adrenergic, H1, and mACh receptors and the monoamine transporters. Importantly, Blonanserin significantly ameliorates the social deficit observed in PCP-administered mice and inhibits the decrease in the levels of Ser897-phosphorylation.

All in all, Blonanserin is a potent and orally active 5-HT2A and dopamine D2 receptor antagonist.


[1]. Holbrook J, et, al. F1000Res. 2019 Jan 28;8:F1000 Faculty Rev-111.

[2]. Martel JC, et, al. Front Pharmacol. 2020 Jul 14;11:1003.