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Keywords:

  • aporphines;
  • docking studies;
  • receptor-binding assays;
  • serotonin receptors;
  • 5-HT2A receptors

Selective blockade of the serotonin 5-HT2A 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-HT2A receptor using AutoDock. Selected compounds with high in silico binding affinities were screened in vitro using radioligand-binding assays against rat serotonin (5-HT1A and 5-HT2A) and dopamine (D1 and D2) receptors. (R)-Roemerine and (±)-nuciferine were found to have high affinity for the 5-HT2A receptor (Ki = 62 and 139 nm, respectively), with (R)-roemerine showing 20- to 400-fold selectivity for the 5-HT2A receptor over the 5-HT1A, 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-HT2A receptor-binding site.