benzofurans and Mood-Disorders

Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist currently under clinical evaluation for the treatment of major depression. This molecule was designed based on the premise that negative feedback circuitry, mediated via 5-HT1 receptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. If the hypothesis is correct, combination of SSRI with 5-HT1A partial agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments. Preclinical in vitro evaluation has confirmed vilazodone's primary pharmacological profile both in clonal and native systems, that is, serotonin reuptake blockade and 5-HT1A partial agonism. However, in vivo and in contrast to combination of 8-OH-DPAT and paroxetine, vilazodone selectively enhanced serotonergic output in the prefrontal cortex of rats. Behavioral evaluations, in the ultrasonic vocalization model of anxiety in rats, demonstrated anxiolytic efficacy. In the forced swim test (a putative model of depression), vilazodone also showed efficacy but at a single dose only. In man, vilazodone abolished REM sleep and demonstrated clinical antidepressant efficacy equivalent to an SSRI. Ongoing clinical evaluations will hopefully reveal whether the founding hypothesis was valid and if vilazodone will produce a more rapid onset of antidepressant efficacy.

Topics: Animals; Antidepressive Agents; Benzofurans; Humans; Indoles; Mood Disorders; Piperazines; Receptor, Serotonin, 5-HT1A; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Vilazodone Hydrochloride

(R)-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane hydrochloride [(-)-BPAP] is a highly potent enhancer of impulse propagation-mediated monoamine release and an inhibitor of monoamine uptake. We evaluated the efficacy of (-)-BPAP as a drug for mood disorders by using two animal models. (1) Acute, but not chronic, administration of (-)-BPAP and imipramine significantly attenuated immobility in mice induced by forced swimming. Chronic, but not acute, administration of (-)-BPAP ameliorated the impairment of social interaction (SI) behavior following forced swimming, without affecting locomotor activity. The ameliorating effect of (-)-BPAP on the impairment of SI behavior was suppressed by dopamine receptor antagonists, which suggests that the effect was mediated through the activation of the dopaminergic system. Chronic administration of imipramine tended to attenuate the impairment of SI behavior in stressed mice, but not significantly. (2) In the olfactory bulbectomized (OB) rat, chronic (-)-BPAP treatment significantly ameliorated the impairment of SI behavior, prepulse inhibition, and tone-cue fear learning, without affecting locomotor activity in an open field and circadian activity pattern. Furthermore, (-)-BPAP tended to improve sexual dysfunction in OB rats, but imipramine had no such effect. These findings suggest that (-)-BPAP may be clinically effective in treating mood disorders, including comorbid anxiety and depression that are poorly responsive to imipramine.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Antidepressive Agents; Behavior, Animal; Benzofurans; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Imipramine; Male; Mice; Mood Disorders; Neural Inhibition; Olfactory Bulb; Rats; Rats, Sprague-Dawley; Reflex, Startle; Social Behavior