Synthesis, biological activity, and molecular modeling of selective 5-HT(2C/2B) receptor antagonists.
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.
Forbes
I T
IT
SmithKline Beecham Pharmaceuticals, Discovery Research, Harlow, Essex, England.
Dabbs
S
S
Duckworth
D M
DM
Ham
P
P
Jones
G E
GE
King
F D
FD
Saunders
D V
DV
Blaney
F E
FE
Naylor
C B
CB
Baxter
G S
GS
Blackburn
T P
TP
Kennett
G A
GA
Wood
M D
MD
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
D007211:Indoles; D011725:Pyridines; D012702:Serotonin Antagonists; C094868:SB 206553