title: 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.
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Hong-xia
authors.initials: HX
authors.lastname: Chen
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China ; Department of Pharmacology, School of Basic Medical Scieneces, Capital Medical University, Beijing, P. R. of China.
authors.forename: Zeng-liang
authors.initials: ZL
authors.lastname: Jin
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Li-ming
authors.initials: LM
authors.lastname: Zhang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Xiao-dan
authors.initials: XD
authors.lastname: Xu
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Zhi-kun
authors.initials: ZK
authors.lastname: Qiu
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China ; Department of Anesthesiology, Chinese PLA 309 Hospital, Beijing, P. R. of China.
authors.forename: Xian-wang
authors.initials: XW
authors.lastname: Wang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: You-zhi
authors.initials: YZ
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Ri-fang
authors.initials: RF
authors.lastname: Yang
authors.affiliation: Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, P. R. of China.
authors.forename: Yun-feng
authors.initials: YF
authors.lastname: Li
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D055808:Drug Discovery; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D000242:Cyclic AMP; D010880:Piperidines; D011728:Pyridones; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C000592342:1-(1-benzyl-4-hydroxypiperidin-4-ylmethyl)-2(1H)-pyridinone