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1053 – In Vitro Receptor-binding Profile Of Lurasidone And Other Commonly-used Antipsychotics

Published online by Cambridge University Press:  15 April 2020

P. Werner
Affiliation:
Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA
T. Ishiyama
Affiliation:
Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan
A. Loebel
Affiliation:
Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA
J. Cucchiaro
Affiliation:
Sunovion Pharmaceuticals Inc., Fort Lee, NJ, USA
T. Horisawa
Affiliation:
Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan
K. Tokuda
Affiliation:
Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan
M. Ogasa
Affiliation:
Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan
T. Ishibashi
Affiliation:
Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan
S.M. Stahl
Affiliation:
Neuroscience Education Institute, University of California San Diego, Carlsbad, CA, USA

Abstract

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Introduction

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-HT2A and 5-HT1A.

Objectives

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

Aims

To compare receptor-binding profiles of antipsychotics.

Methods

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).

Results

Lurasidone displayed potent binding and full antagonism at dopamine D2(Ki, 1.68nM) and serotonin 5-HT2A(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-HT1Areceptors., Lurasidone showed higher affinity for 5-HT7, 5-HT2A, and 5-HT1Areceptors 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).

Conclusions

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.

Type
Abstract
Copyright
Copyright © European Psychiatric Association 2013
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