Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis

Abstract

While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established.

Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis

“…In addition, the maternal Dhcr7 heterozygosity significantly contributed to the observed increase in 7-DHC and 8-DHC and the decrease in desmosterol. The combined increase in 7-DHC and 8-DHC with the decrease in desmosterol is consistent with the known outcome of the DHCR7 enzyme inhibition, as DHCR7 also converts 7-dehydrodesmosterol to desmosterol, thus resulting in a decreased enzyme product [ 10 , 13 ]. In contrast, levels of cholesterol (Fig.…”

“…CAR and ARI have similar pharmacological properties affecting, to different degrees, dopaminergic and serotonergic receptors. They also have similar substructural elements, and favorable clinical outcomes [ 10 ]. However, due to their related structure, they also share a common side effect, the inhibition of the DHCR7 enzyme, the last step in cholesterol synthesis.…”

“…Sterols were analyzed as described previously [ 10 ]. A full description of the sterol analysis method is included in the Supplementary Material .…”

“…In addition to the actions of the G-protein coupled receptors, our previous studies revealed that both CAR and ARI are strong inhibitors of the 7-dehydrocholestrol reductase (DHCR7), the last enzyme in the cholesterol biosynthesis pathway [ 10 , 12 – 15 ]. The common metabolite of CAR and ARI, 2,3-DCPP, inhibits the DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944 [ 10 ]. This DHCR7 inhibition by ARI, CAR, and AY9944 results in the elevation of 7-dehydrocholesterol (7-DHC), which is unstable and can give rise to toxic metabolites [ 16 – 18 ].…”

Desmosterolosis and desmosterol homeostasis in the developing mouse brain

“…Sterol extraction from tissue and LC-MS/MS (SRM) analyses were performed as previously described. 25,[27][28][29]…”