Chemical and in silico exploration of novel 5-hydroxytryptamine 2A receptor (5-HT2AR) ligands
Publication Date
December 13, 2024
Creator
Abstract
The 5-HT2AR is a target in neuropsychiatric conditions such as psychosis, which is commonly managed with atypical antipsychotics. These have associated side effects due to off-target interactions. Consequently, there is a demand to develop therapeutics that exhibit no affinity for these off-target sites. Moreover, in recent 5-HT2AR X-ray crystal structures, a unique hydrophobic pocket or passage between transmembrane helices 4 and 5 sets it apart from other 5-HT2 receptor subtypes. This structural feature is implicated in the selectivity demonstrated by therapeutic pimavanserin towards the 5-HT2AR, owing to its binding conformation. Thus, presenting it as a target to interrogate for enhancing 5-HT2AR binding.
A structure-based approach was used to design a pimavanserin analogue series targeting transmembrane helices 4 and 5. In silico studies involving docking and MM-GBSA calculations using a 5-HT2AR homology model (RMSD 0.09 Å) predicted several analogues to demonstrate improved binding compared to pimavanserin. Synthesis of the series yielded low to moderate yields. To evaluate the binding of the series experimentally a cell membrane-based fluorescent time-resolved Förster resonance energy transfer (TR-FRET) methodology was chosen. This led to the development of a high-affinity 5-HT2AR fluorescent probe, and determination of kinetic rates, (Kd 1.74 ± 0.46 nM, Kon 1.96 ± 0.13 x 108 M−1 min−1, and Koff 0.42 ± 0.02 min−1) characterised at SNAP-tagged human 5-HT2AR expressed in Chinese hamster ovary membranes.
Item Type
ethesis
Thesis Type
PhD
Supervisors
Subjects (LC)
Associated Schools / Departments
School of Pharmacy (UK)
eprints ID
78719
UoN Repository URI
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L_Damerum thesis Chemical and in silico exploration of novel 5-hydroxytryptamine 2A receptor 5-HT2AR ligands final_corrected_V1.pdf
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