title: In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor.
abstract: Triple reuptake inhibitors (TRIs) that inhibit the reuptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are being developed as a new class of antidepressants, which is hypothesized to produce more rapid onset and better efficacy than conventional antidepressants in part due to the addition of the DA component. 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)-ethyl]-phenyl benzoate hydrochloride (PA01), a novel compound, potently bound to the human 5-HT, NE, and DA transporters (Ki=105, 644, and 813nM, respectively), and inhibited the reuptake of 5-HT, NE, and DA into recombinant cells (IC50=341, 427, and 753nM, respectively). In vivo, PA01 dose-dependently decreased immobility time in the forced swimming test (FST) in rats, and the tail suspension test (TST) in mice with higher efficacy than desvenlafaxine succinate (DVS), and showed no stimulatory effect on the spontaneous locomotor activity. The anti-immobility effect of PA01 in the TST was significantly prevented by the pretreatment of mice with DL-p-chlorophenylalanine (pCPA, 300mg/kg, an inhibitor of serotonin synthesis), SCH23390 (0.05mg/kg, s.c., dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., dopamine D2 receptor antagonist). PA01 significantly increased head-twitch response induced by 5-hydroxytryptophan (80mg/kg, i.p., a metabolic precursor to serotonin) in rats, potentiated yohimbine (25mg/kg, s.c., a α2-adrenoceptor antagonist) toxicity, and antagonized high dose apomorphine-induced hypothermia in mice. Taken together, these in vitro and in vivo results indicated that PA01 is a novel triple reuptake inhibitor, and exerts an excellent antidepressant activity in the behavioral despair animal models of depression, with more potent antidepressant activity than DVS at the same dose.
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China; State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Xing
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
authors.forename: Daiying
authors.initials: D
authors.lastname: Zuo
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: yingliang_1016@163.com.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China; School of Pharmacy, Yantai University, Yantai, Shandong 264005, PR China. Electronic address: tianjingwei@luye.cn.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Tian
authors.affiliation: State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China; School of Pharmacy, Yantai University, Yantai, Shandong 264005, PR China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Meng
authors.affiliation: State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China.
authors.forename: Mina
authors.initials: M
authors.lastname: Yang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D003412:Cricetulus; D003511:Cyclohexanols / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000503:physiopathology; D000069468:Desvenlafaxine Succinate; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013045:Species Specificity
chemical_list: D000928:Antidepressive Agents; D003511:Cyclohexanols; D014179:Neurotransmitter Uptake Inhibitors; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine; D000069468:Desvenlafaxine Succinate
keywords: Antidepressant activity; Forced swimming test; PA01; Tail suspension test; Triple reuptake inhibitors