Antidepressant-Like Activity of YL-0919: A Novel Combined Selective Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

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.

Neurochemical and behavioural effects of hypidone hydrochloride (YL‐0919): a novel combined selective 5‐HT reuptake inhibitor and partial 5‐HT1A agonist

“…Our previous studies revealed that hypidone hydrochloride (YL‐0919), a novel small‐molecule compound that showed high affinity and selectivity for both the 5‐HT transporter and 5‐HT 1A receptor, exerted a significant antidepressant effect in various animal models (Chen et al, ; Qin et al, ). Moreover, YL‐0919 was identified as a potential 5‐HT 1A agonist and SSRI.…”

The antidepressant-like activity of AC-5216, a ligand for 18KDa translocator protein (TSPO), in an animal model of diabetes mellitus

“…4), respectively. All of these parameters are represented as depressive-like symptoms in rodents33. Similarly, clinical reports have indicated that depression is linked to hyperglycemia42.…”

“…The test was performed as described previously33. Rats were placed in individual cages to train to consume 1% (w/v) sucrose solution for 48 h without food and water supply.…”

Autoimmune Aspects of Neurodegenerative and Psychiatric Diseases: A Template for Innovative Therapy

“…The genetic studies using 5-HTT knockout animals, therefore, seem to be in conflict with the pharmacological studies using SSRIs. A possible explanation for this discrepancy could be that SSRIs serve as 5-HT receptor (5-HTR) agonists rather than 5-HTT antagonists (126). …”