title: Synthesis, biological activity, and molecular modeling of selective 5-HT(2C/2B) receptor antagonists.
abstract: The synthesis and biological activity are reported for a series of analogues of the previously published indole urea 2 (SB-206553), designed to probe the 5-HT(2C) receptor binding site. Small molecule modeling studies have been used to define a region in space which is allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor. In a complementary approach, docking of 2 into our model of the 5-HT(2C) receptor has allowed us to propose a novel primary binding interaction for this series of diaryl ureas, involving a potential double hydrogen-bonding interaction between the urea carbonyl oxygen of the ligand and two serine residues in the receptor. The difference of two valine residues in the 5-HT(2C) receptor for leucine residues in the 5-HT(2A) receptor is believed to account for the observed 5-HT(2C)/5-HT(2A) selectivity with 2.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Discovery Research, Harlow, Essex, England.
authors.forename: I T
authors.initials: IT
authors.lastname: Forbes
authors.forename: S
authors.initials: S
authors.lastname: Dabbs
authors.forename: D M
authors.initials: DM
authors.lastname: Duckworth
authors.forename: P
authors.initials: P
authors.lastname: Ham
authors.forename: G E
authors.initials: GE
authors.lastname: Jones
authors.forename: F D
authors.initials: FD
authors.lastname: King
authors.forename: D V
authors.initials: DV
authors.lastname: Saunders
authors.forename: F E
authors.initials: FE
authors.lastname: Blaney
authors.forename: C B
authors.initials: CB
authors.lastname: Naylor
authors.forename: G S
authors.initials: GS
authors.lastname: Baxter
authors.forename: T P
authors.initials: TP
authors.lastname: Blackburn
authors.forename: G A
authors.initials: GA
authors.lastname: Kennett
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
mesh_terms: D000818:Animals; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry; D011869:Radioligand Assay; D051381:Rats; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D007211:Indoles; D011725:Pyridines; D012702:Serotonin Antagonists; C094868:SB 206553