Valnoctamide, a non‐teratogenic amide derivative of valproic acid, inhibits arachidonic acid activationin vitroby 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 (Acsl)-4 at Ki of 25 mM. Inhibition may account for VPA’s ability to reduce AA turnover in brain phospholipids of unanesthetized rats at a therapeutically relevant dose. VPA is teratogenic. We now 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 E. 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 Ki equal 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.

A randomized, double‐blind, placebo‐ and risperidone‐controlled study on valnoctamide for acute mania

“…showed that valnoctamide works as a myo‐inositol‐1‐phosphate (MIP) synthase inhibitor similar to VPA, thus suggesting that valnoctamide does have characteristics in common with VPA, an action consistent with the inositol hypothesis of lithium . Another shared mechanism has been suggested by Modi and colleagues, who noted that arachidonic acid (AA) may be elevated in bipolar disease, and that valnoctamide (at high concentrations) downregulates AA . Existing mood stabilizers, including VPA and carbamazepine, may downregulate AA, hence improving the symptoms of bipolar disorder.…”

“…24 Another shared mechanism has been suggested by Modi and colleagues, who noted that arachidonic acid (AA) may be elevated in bipolar disease, and that valnoctamide (at high concentrations) downregulates AA. 13 Existing mood stabilizers, including VPA and carbamazepine, may downregulate AA, hence improving the symptoms of bipolar disorder. Our failure to show efficacy for valnoctamide might constitute evidence against a shared mechanism, but also might be just be due to a mechanism of action specific to VPA, and not shared by valnoctamide.…”

“…Valnoctamide is a VPA amide derivative that, in contrast to VPA, has been shown to be non‐teratogenic in mice and rabbits. In rats, a modest teratogenic signal was observed at plasma concentrations 15 times higher than valnoctamide therapeutic plasma levels . One previous randomized clinical trial compared valnoctamide vs placebo as an adjunct to risperidone in 41 patients with bipolar disorder, and found greater efficacy of valnoctamide when compared to placebo .…”

“…In rats, a modest teratogenic signal was observed at plasma concentrations 15 times higher than valnoctamide therapeutic plasma levels. [11][12][13][14][15][16] One previous randomized clinical trial compared valnoctamide vs placebo as an adjunct to risperidone in 41 patients with bipolar disorder, and found greater efficacy of valnoctamide when compared to placebo. 17 At present, no study has examined the effect of valnoctamide monotherapy in bipolar disorder.…”

Valnoctamide, which reduces rat brain arachidonic acid turnover, is a potential non-teratogenic valproate substitute to treat bipolar disorder

“…In vitro , VCD selectively and uncompetitively inhibited activation of AA to AA-CoA by recombinant Acsl-4 at a lower K i than that of VPA (Modi et al, 2014). …”