S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models.
BACKGROUND
Serotonin (5-HT)(2C) receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states.


OBJECTIVE
Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006.


METHODS
Standard cellular, electrophysiological, neurochemical, and behavioral procedures were used.


RESULTS
S32006 displayed high affinity for human (h)5-HT(2C) and h5-HT(2B) receptors (pK (i)s, 8.4 and 8.0, respectively). By contrast, it had negligible (100-fold lower) affinity for h5-HT(2A) receptors and all other sites examined. In measures of Gq-protein coupling/phospholipase C activation, S32006 displayed potent antagonist properties at h5-HT(2C) receptors (pK (B) values, 8.8/8.2) and h5-HT(2B) receptors (7.8/7.7). In vivo, S32006 dose-dependently (2.5-40.0 mg/kg, i.p. and p.o.) abolished the induction of penile erections and a discriminative stimulus by the 5-HT(2C) receptor agonist, Ro60,0175, in rats. It elevated dialysis levels of noradrenaline and dopamine in the frontal cortex of freely moving rats, and accelerated the firing rate of ventrotegmental dopaminergic and locus ceruleus adrenergic neurons. At similar doses, S32006 decreased immobility in a forced-swim test in rats, reduced the motor depression elicited by 5-HT(2C) and alpha(2)-adrenoceptor agonists, and inhibited both aggressive and marble-burying behavior in mice. Supporting antidepressant properties, chronic (2-5 weeks) administration of S32006 suppressed "anhedonia" in a chronic mild stress procedure and increased both expression of BDNF and cell proliferation in rat dentate gyrus. Finally, S32006 (0.63-40 mg/kg, i.p. and p.o) displayed anxiolytic properties in Vogel conflict and social interaction tests in rats.


CONCLUSIONS
S32006 is a potent 5-HT(2C) receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models.
Dekeyne
Anne
A
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, Croissy/Seine, France. anne.dekeyne@fr.netgrs.com
Mannoury la Cour
Clotilde
C
Gobert
Alain
A
Brocco
Mauricette
M
Lejeune
Françoise
F
Serres
Florence
F
Sharp
Trevor
T
Daszuta
Annie
A
Soumier
Amélie
A
Papp
Mariusz
M
Rivet
Jean-Michel
JM
Flik
Gunnar
G
Cremers
Thomas I
TI
Muller
Olivier
O
Lavielle
Gilbert
G
Millan
Mark J
MJ
D000374:Aggression / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D015306:Biogenic Monoamines / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D003220:Conflict, Psychological; D006224:Cricetinae; D003412:Cricetulus; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044403:Receptor, Serotonin, 5-HT2B / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000187:drug effects; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013550:Swimming / Q000523:psychology; D014828:Vocalization, Animal
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D015306:Biogenic Monoamines; D019208:Brain-Derived Neurotrophic Factor; D007211:Indoles; D011725:Pyridines; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011994:Recombinant Proteins; C533966:S32006; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists