title: Pharmacokinetic profiles contribute to the differences in behavioral pharmacology of 071031B enantiomers as novel serotonin and norepinephrine reuptake inhibitors.
abstract: Our previous study indicated that a chiral compound 071031B was a novel serotonin and noradrenaline reuptake inhibitor with superior antidepressant activity compared to duloxetine. The present study aimed to investigate chiral pharmacology differences of 071031B enantiomers, S-071031B and R-071031B, and disclose mechanisms underlying the behavioral differences based on target profiles and pharmacokinetic profiles. In vivo behavioral tests indicated that S-071031B was more potent than R-071031B in two depression models (the forced swimming test in mice and rats) and two pain models (the acetic acid-induced writhing and formalin tests in mice). In vitro assays revealed that both S-071031B and R-071031B showed high affinity for human serotonin transporters and norepinephrine transporters with equal potency, and showed consistently equipotent inhibitory effects on serotonin and norepinephrine uptake. Pharmacokinetic studies demonstrated that oral availability and hepatic metabolism, rather than pH stability, intestinal transport, and plasma binding, contributed to enantiomers' behavioral differences. Based on these findings, it is suggested that S-071031B is a more active enantiomer, and the differential pharmacokinetic profiles, but not target affinity, contribute to differences of S-071031B and R-071031B in behavioral pharmacology. Moreover, current PK-PD study may provide positive exploration for chiral antidepressants development.
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xue
authors.affiliation: 2 Pharmaceutical Department, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: 3 Department of Drug Synthesis, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: He
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Zeng-Liang
authors.initials: ZL
authors.lastname: Jin
authors.affiliation: 3 Department of Drug Synthesis, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Fan
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Nuo-Min
authors.initials: NM
authors.lastname: Li
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yuan
authors.affiliation: 2 Pharmaceutical Department, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Ai-Ping
authors.initials: AP
authors.lastname: Zheng
authors.affiliation: 3 Department of Drug Synthesis, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Bo-Hua
authors.initials: BH
authors.lastname: Zhong
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Department of New Drug Evaluation, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism; D000068736:Duloxetine Hydrochloride / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013550:Swimming / Q000502:physiology; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: C585814:071031B compound; D000928:Antidepressive Agents; D052117:Benzodioxoles; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D013876:Thiophenes; D012701:Serotonin; D000068736:Duloxetine Hydrochloride; D009638:Norepinephrine
keywords: Antidepressants; behavioral pharmacology; chiral pharmacology; pharmacokinetics; serotonin and norepinephrine uptake inhibitors