A role for rebinding in the prevalence of on-target side effects of clinically used antipsychotics

Sykes, David A (2020) A role for rebinding in the prevalence of on-target side effects of clinically used antipsychotics. PhD thesis, University of Nottingham.

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Abstract

One explanation as to why atypical antipsychotic drugs (APDs e.g. clozapine) show reduced extrapyramidal side effects (EPS) involves their rapid dissociation from the dopamine D2 receptor (D2R). Their selective regional action in the brain permits an antipsychotic effect through inhibition of mesolimbic dopamine signalling but spares physiological dopamine neurotransmission in the striatum. This hypothesis is based largely on direct kinetic measurements using radiolabelled APDs and achieved under varied conditions and over many years. The alternative, ‘serotonin-dopamine hypothesis’ of atypicality suggests that antagonism at the 5-HT2A receptor and agonism at the 5-HT1A receptor may account for reduced EPS, due to increased nigrostriatal dopamine release. The strength of this hypothesis is currently limited to a consideration of the relative receptor affinities of APDs for the 5-HT2A and dopamine D2R, and limited data exploring their 5-HT1A agonist effects.

To further explore these hypotheses, I developed a series of novel higher throughput time-resolved fluorescence resonance energy transfer (TR-FRET) binding assays to measure the kinetic properties of a series of clinically relevant typical and atypical APDs at the dopamine D2R, the serotonin 5-HT2A and 5-HT1A receptors. Relative 5-HT1AR APD efficacy was estimated using a [35S]-GTPS assay and through the application of the operational model of agonism. These studies establish a novel mechanism of atypical APD action based on a restricted drug diffusion model, suggesting that for the majority of clinically used APDs association rate and not dissociation rate, better predicts the overall rate of dopamine D2R reversal in the striatum.

For compounds with negligible affinity for 5-HT2A receptors, EPS is robustly predicted by a D2R specific rebinding model that integrates D2R association and dissociation rates, to calculate the net rate of reversal of receptor blockade (kr). However, I show that for certain compounds (eg sertindole) a combination of high relative 5-HT2A occupancy and rapid dopamine D2R dissociation (koff), equates to a reduced propensity to cause EPS. Thus, optimizing the binding kinetics of compounds at both the serotonin 5-HT2A and the dopamine D2R may result in the development of APDs with an improved on-target side-effect profile.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Hill, Stephen J
Charlton, Steven J
Keywords: G protein coupled receptor, Kinetics, Association rate constant, Dissociation rate constant, Anti-psychotics, Side effects, Rebinding
Subjects: Q Science > QP Physiology > QP501 Animal biochemistry
R Medicine > RM Therapeutics. Pharmacology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID: 60636
Depositing User: Sykes, David
Date Deposited: 18 Aug 2020 10:52
Last Modified: 18 Aug 2020 10:52
URI: http://eprints.nottingham.ac.uk/id/eprint/60636

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