title: Structure-based identification of aporphines with selective 5-HT(2A) receptor-binding activity.
abstract: 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 nM, 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.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Vani
authors.initials: V
authors.lastname: Munusamy
authors.forename: Beow Keat
authors.initials: BK
authors.lastname: Yap
authors.forename: Michael J C
authors.initials: MJ
authors.lastname: Buckle
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Doughty
authors.forename: Lip Yong
authors.initials: LY
authors.lastname: Chung
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001060:Aporphines / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006860:Hydrogen Bonding; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D001060:Aporphines; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; C030169:roemerine; C008692:nuciferine