Atypical antipsychotics bind to multiple receptor types and subtypes. Improved outcomes in schizophrenia are linked to activity at D₂ and serotonin receptors 5-HT₇, 5-HT_2A and 5-HT_1A.

To characterize the receptor-binding profile of lurasidone and other antipsychotics.

To compare receptor-binding profiles of antipsychotics.

Replicated, side-by-side receptor-binding assays used human recombinant receptors (for 5-HT₇, α₂A, and α₂C) or membrane-fractions of animal CNS tissue. Affinities were determined via Hill plot analysis for IC⁵⁰values; Ki values were determined using Ki=IC₅₀/(1+ S/Kd) (S=concentration of competing radioligand, Kd=dissociation constant).

Lurasidone displayed potent binding and full antagonism at dopamine D₂(Ki, 1.68nM) and serotonin 5-HT_2A(Ki, 2.03nM) receptors (the highest D₂affinity of all tested agents). Lurasidone's dopamine binding was selective for D₂receptors. Unlike other antipsychotics tested, lurasidone had very high affinity and full antagonism at serotonin 5-HT₇(Ki, 0.49nM), and nanomolar affinity (Ki=6.75nM) with weak-moderate partial agonism at serotonin 5-HT_1Areceptors., Lurasidone showed higher affinity for 5-HT₇, 5-HT_2A, and 5-HT_1Areceptors relative to D₂receptor-binding than other agents. Lurasidone displayed moderate affinity for α₂C adrenoceptors (Ki, 10.8nM); moderate-weak affinity for α₁adrenoceptors (Ki, 48nM); and minimal or unappreciable affinity for receptors associated with undesirable effects (5-HT₂C [Ki, 415nM], histamine H₁[IC₅₀>1000nM] and muscarinic [cholinergic] M₁[IC₅₀>1000nM] receptors).

The unique pharmacological profile of lurasidone is consistent with observed antipsychotic efficacy, low-tomoderate likelihood of EPS, low weight-gain potential, and possible mood, anxiety, and cognitive benefits.