Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats.
E-6837 is a novel, selective and high-affinity 5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT(6) receptor and full agonism at a constitutively active human 5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (-6.6%) remained lower than after sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. These results show that the 5-HT(6) receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.
Fisas
Angels
A
Laboratorios Dr. Esteve S.A., Av. Mare de Déu de Montserrat 221, 08041 Barcelona, Spain.
Codony
Xavier
X
Romero
Gonzalo
G
Dordal
Alberto
A
Giraldo
Jesus
J
Mercé
Ramon
R
Holenz
Jörg
J
Vrang
N
N
Sørensen
R V
RV
Heal
David
D
Buschmann
Helmut
H
Pauwels
Petrus Johan
PJ
D000818:Animals; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D003216:Conditioning, Operant / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D003503:Cyclobutanes / Q000494:pharmacology; D004032:Diet; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy* / Q000523:psychology*; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013649:Taste / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects*
D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D001786:Blood Glucose; D003503:Cyclobutanes; D007211:Indoles; D008055:Lipids; C500059:N-(3-(2-dimethylaminoethyl)-1H-indol-5-yl)-5-chloronaphthalene-2-sulfonamide; D011985:Receptors, Serotonin; D013449:Sulfonamides; D013876:Thiophenes; C097216:serotonin 6 receptor; D012701:Serotonin; D000242:Cyclic AMP; C117443:SB 271046; C058254:sibutramine