PT  - JOURNAL ARTICLE
AU  - Lauth, Matthias
AU  - Rohnalter, Verena
AU  - Bergström, Åsa
AU  - Kooshesh, Mahsa
AU  - Svenningsson, Per
AU  - Toftgård, Rune
TI  - Antipsychotic Drugs Regulate Hedgehog Signaling by Modulation of 7-Dehydrocholesterol Reductase Levels
AID  - 10.1124/mol.110.066431
DP  - 2010 Sep 01
TA  - Molecular Pharmacology
PG  - 486--496
VI  - 78
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/78/3/486.short
4100  - http://molpharm.aspetjournals.org/content/78/3/486.full
SO  - Mol Pharmacol2010 Sep 01; 78
AB  - Recently we identified GANT61, a small-molecule antagonist of Gli transcription factors, which are the final effectors of the mammalian Hedgehog (HH) signaling pathway. Here we describe a diamine substructure of GANT61 that carries the biological activity and show that this part of the molecule is structurally related to trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride (AY9944), an inhibitor of the enzymatic activity and transcriptional inducer of 7-dehydrocholesterol-reductase (Dhcr7, EC 1.3.1.21). Treatment of cells with the GANT61 diamine, AY9944, or overexpression of DHCR7 results in the attenuation of Smoothened-dependent and -independent HH signaling. Whereas GANT61 function is independent of Dhcr7, AY9944 does require up-regulation of endogenous Dhcr7. In line with these findings, Dhcr7-modulating antipsychotic (clozapine, chlorpromazine, haloperidol) and antidepressant (imipramine) drugs regulate HH signaling in vitro and in vivo. Modulation of HH signaling may represent a hitherto undiscovered biological (side) effect of therapeutics used to treat schizophrenia and depression.