Get access

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

Authors

  • Vani Munusamy,

    1. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
    Search for more papers by this author
  • Beow Keat Yap,

    1. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
    2. School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 USM, Pulau Pinang, Malaysia
    Search for more papers by this author
  • Michael J. C. Buckle,

    Corresponding author
    1. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
      Corresponding authors: Michael J. C. Buckle, buckle@um.edu.my ; Lip Yong Chung, chungly@um.edu.my
    Search for more papers by this author
  • Stephen W. Doughty,

    1. The School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor, Malaysia
    Search for more papers by this author
  • Lip Yong Chung

    Corresponding author
    1. Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
      Corresponding authors: Michael J. C. Buckle, buckle@um.edu.my ; Lip Yong Chung, chungly@um.edu.my
    Search for more papers by this author

Corresponding authors: Michael J. C. Buckle, buckle@um.edu.my ; Lip Yong Chung, chungly@um.edu.my

Abstract

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.

Get access to the full text of this article

Ancillary