Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor.

Tim J Fyfe,Steven J Charlton,Peter J Scammells,Shailesh N Mistry,J Robert Lane,Barrie Kellam,Ben Capuano,David A Sykes

doi:10.1021/acs.jmedchem.9b00864

Abstract

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side effects (EPSs) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R, whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and revealed that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimization of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.

Highlights

Haloperidol (1, Figure 1) is an effective, typical antipsychotic drug (APD) used in the treatment of schizophrenia (SCZ)
We found that the association rates of the APDs varied over three orders of magnitude and that association rates, rather
We show that there is no correlation between kon and the 10 physicochemical parameters clogP and TPSA, meaning that differences in kinetic profiles and corresponding compound affinities are not due to non-specific effects such as cell membrane binding

Summary

Introduction

Haloperidol (1, Figure 1) is an effective, typical antipsychotic drug (APD) used in the treatment of schizophrenia (SCZ). As for all current APDs, its mechanism of action is primarily through antagonism of dopamine (DA) D2 receptors (D2R) in the mesolimbic pathway, where excessive DA activity is thought to underlie the positive symptoms of schizophrenia.. 1 along with other typical APDs, are associated with severe on-target side effects including EPS (e.g., Parkinsonian symptoms such as bradykinesia and tremor) and hyperprolactinemia.. 1 along with other typical APDs, are associated with severe on-target side effects including EPS (e.g., Parkinsonian symptoms such as bradykinesia and tremor) and hyperprolactinemia.3,4 These symptoms are mediated by blockade of D2R signalling in the nigrostriatal and tuberoinfundibular DA pathways, respectively.. Atypical APDs display a diminished incidence of EPS and hyperprolactinemia relative to typical.

Objectives

Methods

Results

Conclusion