Abstract
It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder.
Highlights
Major depression is the one of the most common psychiatric diseases with a life-time prevalence of 15–20%, and is predicted to increase from fourth to second highest global burden of disease by 2030 [1,2]
The results showed that YL-0919 bound to 5-HT1A receptor and serotonin transporter with high affinity, but its affinity to norepinephrine transporter (NET) and DAT were low, blocking [3H]nisoxetine and [3H]win35428 binding with Ki values of 650612 nM and 26526112 nM respectively (Table 3)
The receptor binding studies demonstrated that YL-0919 displayed high affinity for rat 5-HT1A receptor and serotonin transporter, whereas showed low affinity to NET, DAT, and other G protein coupled receptors, suggesting the dual-target binding profile of YL-0919
Summary
Major depression is the one of the most common psychiatric diseases with a life-time prevalence of 15–20%, and is predicted to increase from fourth to second (first in high income countries) highest global burden of disease by 2030 [1,2]. Selective monoamine uptake inhibitors are being used as principle therapeutic agents in the treatment of depression [3]. Tricyclic antidepressants developed earlier acted by enhancing both serotonin and norepinephrine transmissions [6]. Due to their nonspecific interactions with multiple central nervous system (CNS) receptors, they exhibit unwanted side effects which limit their use in the clinics [7]. Development of selective serotonin reuptake inhibitors (SSRIs) alleviated many of the side effects exhibited by traditional tricyclic antidepressants and proved to be more effective [8,9]. Considerable efforts are invested in the search for better drugs for more effective treatment of depression
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