Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.
The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.
Bromidge
S M
SM
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, England.
Dabbs
S
S
Davies
D T
DT
Duckworth
D M
DM
Forbes
I T
IT
Ham
P
P
Jones
G E
GE
King
F D
FD
Saunders
D V
DV
Starr
S
S
Thewlis
K M
KM
Wyman
P A
PA
Blaney
F E
FE
Naylor
C B
CB
Bailey
F
F
Blackburn
T P
TP
Holland
V
V
Kennett
G A
GA
Riley
G J
GJ
Wood
M D
MD
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003220:Conflict, Psychological; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012919:Social Behavior; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D007211:Indoles; D011725:Pyridines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C112099:SB 221284; D012702:Serotonin Antagonists