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Structure‐Based Identification of Aporphines with Selective 5‐HT 2A Receptor‐Binding Activity
Author(s) -
Munusamy Vani,
Yap Beow Keat,
Buckle Michael J. C.,
Doughty Stephen W.,
Chung Lip Yong
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12069
Subject(s) - receptor , dopamine receptor d2 , 5 ht receptor , chemistry , radioligand , docking (animal) , dopamine receptor d3 , radioligand assay , binding site , stereochemistry , serotonin , homology modeling , pharmacology , biochemistry , biology , medicine , enzyme , nursing
Selective blockade of the serotonin 5‐HT 2A receptor is a useful therapeutic approach for a number of disorders, including schizophrenia, insomnia and ischaemic heart disease. A series of aporphines were docked into a homology model of the rat 5‐HT 2A receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand‐binding assays against rat serotonin (5‐HT 1A and 5‐HT 2A ) and dopamine (D1 and D2) receptors. ( R )‐Roemerine and (±)‐nuciferine were found to have high affinity for the 5‐HT 2A receptor ( K i = 62 and 139 n m , respectively), with ( R )‐roemerine showing 20‐ to 400‐fold selectivity for the 5‐HT 2A receptor over the 5‐HT 1A , D1 and D2 receptors. Investigation into the ligand–receptor interactions suggested that the selectivity of ( R )‐roemerine is due to it having stronger H‐bonding and dipole–dipole interactions with several of the key residues in the 5‐HT 2A receptor‐binding site.