SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Abstract

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (7) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT 1A/B receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED 50 of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [ 3 H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (po0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

Pharmacological Effects of Lu AA21004: A Novel Multimodal Compound for the Treatment of Major Depressive Disorder

“…In the rat social interaction test, short-term administration of Lu AA21004 displayed an anxiolytic-like effect similar to that of chlordiazepoxide. In contrast, an anxiolytic-like effect by SSRIs or SNRIs usually requires subchronic or chronic treatment in this model (Artaiz et al, 2005;Starr et al, 2007). The selective 5-HT 3 antagonist BRL 46470A exerts an short-term anxiolytic-like activity in the rat social interaction test (Blackburn et al, 1993).…”

Assessment of luteolin (3′,4′,5,7-tetrahydroxyflavone) neuropharmacological activity

“…However, Luteolin, despite its low affinity for the BDZ-R, seems to have anxiolytic-like effects or, at least, to interact with different neurotransmitter systems so as to induce CNS effects. Another neurotransmitter system such as the 5-HT receptors [65,66] could be involved in its action, and this should be further investigated. On the contrary, we must consider that flavonoids are subject to intense metabolism [67] and after oral administration of luteolin to rats, free luteolin has been determined in plasma but also luteolin's sulfate and glucoronate derivatives (the main metabolite was found to be a luteolin monoglucoronate) as well as o-methyl luteolin, with the dose administered strongly affecting the type of metabolites formed [68].…”

Identification of dual active agents targeting 5-HT1A and SERT by combinatorial virtual screening methods

“…However, the efficacies of anti-depressants in current market are greatly reduced by their delayed onset of action and undesirable side effects [4]. As reported, negative feedback control of 5-HT1A autoreceptors can decrease the concentration of 5HT on nerve terminal, which further led to a delayed onset of antidepressant [4]. Therefore, multi-target drugs simultaneously targeting both 5-HT1A and serotonin transporter (SERT) may propose a novel strategy with enhanced efficacy.…”

“…Several drugs are now available for major depression, majority of which are selective serotonin reuptake inhibitors (SSRIs) [3]. However, the efficacies of anti-depressants in current market are greatly reduced by their delayed onset of action and undesirable side effects [4]. As reported, negative feedback control of 5-HT1A autoreceptors can decrease the concentration of 5HT on nerve terminal, which further led to a delayed onset of antidepressant [4].…”