2,3,4,5-tetrahydro- and 2,3,4,5,11,11a-hexahydro-1H-[1,4]diazepino[1,7-a]indoles: new templates for 5-HT(2C) agonists.
The design and synthesis of the novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole 5 is described. This azepinoindole has excellent affinity for 5-HT(2C) (K(i) 4.8 nM) and modest selectivity over 5-HT(2A) ( approximately 4-fold). Several N- and C(11)-substituted analogues of 5 were prepared, as were a number of biaryl indoline derivatives. The anxiolytic potential for the azepinoindole template 5 is demonstrated by activity in a mouse shock-aggression assay.
Ennis
Michael D
MD
Medicinal Chemistry III, Pharmacia Corporation, 301 Henrietta Street, 49009, Kalamazoo, MI, USA. d.ennis@pharmacia.com
Hoffman
Robert L
RL
Ghazal
Nabil B
NB
Olson
Rebecca M
RM
Knauer
Christopher S
CS
Chio
Chris L
CL
Hyslop
Deborah K
DK
Campbell
Jeffery E
JE
Fitzgerald
Lawrence W
LW
Nichols
Nanette F
NF
Svensson
Kjell A
KA
McCall
Robert B
RB
Haber
Christopher L
CL
Kagey
Michelle L
ML
Dinh
Dac M
DM
D000374:Aggression / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001259:Ataxia / Q000139:chemically induced; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004597:Electroshock; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C481399:2,3,4,5,11,11a-hexahydro-1H-(1,4)diazepino(1,7-a)indole; C481398:2,3,4,5-tetrahydro-1H-(1,4)diazepino(1,7-a)indole; D014151:Anti-Anxiety Agents; D001381:Azepines; D007202:Indicators and Reagents; D007211:Indoles; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017366:Serotonin Receptor Agonists