Structure‐Based Identification of Aporphines with Selective 5‐HT2A Receptor‐Binding Activity

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.