Abstract
Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D2 receptor may result in APDs with improved therapeutic profile.
Highlights
Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor
Specific binding of the agonist PPHT-red to human D2L receptor expressed in Chinese hamster ovary (CHO) membranes was saturable and best described by the interaction of the fluorescent ligand with a single population of a Clozapine (–) Sulpiride Ziprasidone Haloperidol (+) Butaclamol Flupenthixol Molindone
It has been widely assumed that association rates for APDs are diffusion limited and comparable, meaning that the dissociation rate determines their affinity[37, 38]
Summary
Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. Several different pharmacological theories have been proposed to account for the atypicality of SGAs. One proposed mechanism is antagonism of the 5-HT2A receptor, which is thought to “balance” striatal dopamine signaling and reduce extrapyramidal side effects (EPS)[9,10,11]. The observation that the SGA amisulpride, which is considerably more D2 selective over 5-HT2A yet still exhibits reduced EPS, suggests that this theory cannot account for all examples of atypicality[12, 13] Another enduring theory of atypicality is based on the dissociation kinetics of APDs from the D2R. This concept originated from the observation that some atypical APDs have lower affinity demonstrated for to btheedDue2RtothaanfasttyepricdailssAoPciDatsi1o4n–1r6a, twe1h7i–c1h9
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