@article {Lauth486, author = {Matthias Lauth and Verena Rohnalter and {\r A}sa Bergstr{\"o}m and Mahsa Kooshesh and Per Svenningsson and Rune Toftg{\r a}rd}, title = {Antipsychotic Drugs Regulate Hedgehog Signaling by Modulation of 7-Dehydrocholesterol Reductase Levels}, volume = {78}, number = {3}, pages = {486--496}, year = {2010}, doi = {10.1124/mol.110.066431}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/78/3/486}, eprint = {https://molpharm.aspetjournals.org/content/78/3/486.full.pdf}, journal = {Molecular Pharmacology} }