5-HT2C receptor agonists: pharmacological characteristics and therapeutic potential.
In vitro, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 exhibited high-affinity binding to the serotonin2C (5HT2C) receptors and stimulated turnover of inositol 1,4,5-triphosphate. Affinity to several of the other 5-HT receptor subtypes and to numerous nonserotonergic receptors was much lower. In rats, both compounds elicited behavioral signs of 5-HT2C receptor agonism but not 5-HT2A receptor agonism. Hypomotility induced in rats by high doses of these compounds was reversed by the 5-HT2C receptor antagonist N-(2-naphthyl)-N'-(3-pyridyl)-urea 1:1 HCI. In addition, these compounds were active in tests used to demonstrate anticompulsive effects: reducing schedule-induced polydipsia in rats (prevented by the 5-HT2C/2B receptor antagonist N-(1-methyl-5'-indolyl)-(3-pyridyl)urea 1:1 HCl, reversing increased scratching induced with 8-hydroxy-dipropylaminotetralin 1:1 HCl in squirrel monkeys (no tolerance developed), decreasing responding in the marble-burying task in mice, and decreasing excessive eating of palatable food in rats. In contrast to these compounds, fluoxetine was much less potent, and in some tasks less efficacious, in reducing excessive behavior in these models. These two 5-HT2C receptor agonists do not show anxiogenic effects in the plus-maze in rats. (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 reduced the olfactory bulbectomy-induced passive avoidance impairment in rats, a result that indicates antidepressant potential. Similarly, in the differential-reinforcement-of-low rate 72-s operant schedule task in rats, (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 increased (and (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1, 2-b]pyrrol-1-yl)-1-methylethylamine 1:1 C4H4O4 showed a tendency to increase) total reinforcements received, which is suggestive of antidepressant activity. The electroencephalography defined sleep-waking pattern in rats produced by these two 5-HT2C agonists, as well as fluoxetine, included increased quiet-waking and decreased rapid-eye-movement sleep, which is characteristic of antidepressant drugs. These results suggest that 5-HT2C receptor agonism is associated with therapeutic potential in obsessive compulsive disorder and depression.
Preclinical CNS Research Department, Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
J R
JR
Martin
M
M
Bös
F
F
Jenck
J
J
Moreau
V
V
Mutel
A J
AJ
Sleight
J
J
Wichmann
J S
JS
Andrews
H H
HH
Berendsen
C L
CL
Broekkamp
G S
GS
Ruigt
C
C
Köhler
A M
AM
Delft
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D009830:Olfactory Bulb / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012453:Saimiri; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D012890:Sleep / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D009281:Naphthalenes; C506337:RO 60-0491; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014508:Urea