title: Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4.
abstract: OBJECTIVE
  Valproic acid (VPA), a mood stabilizer used for treating bipolar disorder (BD), uncompetitively inhibits acylation of arachidonic acid (AA) by recombinant AA-selective acyl-CoA synthetase 4 (Acsl4) at an enzyme inhibition constant (Ki ) of 25 mM. Inhibition may account for VPA's ability to reduce AA turnover in brain phospholipids of unanesthetized rats and to be therapeutic in BD. However, VPA is teratogenic. We tested whether valnoctamide (VCD), a non-teratogenic amide derivative of a VPA chiral isomer, which had antimanic potency in a phase III BD trial, also inhibits recombinant Acsl4.
  
  
  METHODS
  Rat Acsl4-flag protein was expressed in Escherichia coli. We used Michaelis-Menten kinetics to characterize and quantify the ability of VCD to inhibit conversion of AA to AA-CoA by recombinant Acsl4 in vitro.
  
  
  RESULTS
  Acsl4-mediated activation of AA to AA-CoA by Acsl4 was inhibited uncompetitively by VCD, with a Ki of 6.38 mM.
  
  
  CONCLUSIONS
  VCD's ability to uncompetitively inhibit AA activation to AA-CoA by Acsl4, at a lower Ki than VPA, suggests that, like VPA, VCD may reduce AA turnover in rat brain phospholipids. If so, VCD and other non-teratogenic Acsl4 inhibitors might be considered further for treating BD.
authors.affiliation: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Hiren R
authors.initials: HR
authors.lastname: Modi
authors.forename: Mireille
authors.initials: M
authors.lastname: Basselin
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007456:Iodine Isotopes / Q000378:metabolism; D015233:Models, Statistical; D014635:Valproic Acid
chemical_list: D000577:Amides; D007456:Iodine Isotopes; D016718:Arachidonic Acid; C045179:valnoctamide; D014635:Valproic Acid; D003066:Coenzyme A Ligases
keywords: Michaelis-Menten kinetics; acyl-CoA synthetase 4; anticonvulsant; arachidonic acid; bipolar disorder; brain; cascade; enzyme; inhibition; metabolism; mood stabilizer; rat; valnoctamide; valproate