amibegron and Depressive-Disorder

SR 58611A [SR 58611], a highly selective agonist for atypical beta3-adrenoceptors, inhibits intestinal motility. This (phenylethanol) aminotetraline sympathomimetic was originated by Sanofi as a potential treatment for irritable bowel syndrome but is now in development for depression. SR 58611A is currently in phase III trials for depression in France. A phase IIa trial of SR 58611A in patients with severe recurrent depression showed it to be superior to fluoxetine and well tolerated, while a phase IIb trial demonstrated comparable efficacy and tolerability to paroxetine. SR 58611A was in phase II clinical trials in France for irritable bowel syndrome but there is no record of active development of SR 58611A for this indication. SR 58611A had also been in phase IIa for the treatment of obesity but no recent development has been reported for this indication. SR 58878 is the acid metabolite of SR 58611A.

Topics: Adrenergic beta-3 Receptor Antagonists; Animals; Antidepressive Agents; Clinical Trials as Topic; Depressive Disorder; Gastric Acid; Gastrointestinal Motility; Humans; Obesity; Tetrahydronaphthalenes

The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.

Topics: Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Aggression; Animals; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Anxiety Disorders; Behavior, Animal; Cognition; Depressive Disorder; Diazepam; Ethanol; Exploratory Behavior; Fluoxetine; Gerbillinae; Imipramine; Interpersonal Relations; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Adrenergic, beta-3; Sleep; Substance-Related Disorders; Swimming; Tetrahydronaphthalenes