Derivatization of common antidepressant drugs increases inhibition of acid sphingomyelinase and reduces induction of phospholipidosis
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In recent studies, major depressive disorder (MDD) was linked to an increase in acid sphingomyelinase (ASM) activity. Several drugs that are commonly used to treat MDD functionally inhibit the lysosomal enzyme ASM and are called functional inhibitors of ASM (FIASMAs). These drugs are classified as cationic amphiphilic drugs (CADs) that influence the catalytic activities of different lysosomal enzymes. This action results in the side effect of phospholipidosis (PLD), which describes a detrimental increase in the phospholipid content in lysosomes. FIASMAs differ only slightly in their physico-chemical properties, but their effects on ASM activity and induction of the lysosomal phospholipid content vary significantly. In this study, we systematically induced minor chemical modifications to the FIASMAs imipramine, desipramine and fluoxetine. We generated a library of 45 new CADs with slightly different log P (logarithmic partition coefficient) and pKa (logarithmic acid dissociation constant) values. The effects of the compounds on the ASM activity and lysosomal phospholipid content were assessed in cell culture assays. We identified four compounds with beneficial effects, i.e., increased ASM activity inhibition and reduced PLD induction compared with the original drugs. The compounds HT04, RH272B and RH272D outperformed the original imipramine, whereas RH281A performed better than desipramine. Thus, minor chemical variations of CADs impact lysosomal metabolism in a specific manner and can lead to antidepressant drugs with less deleterious side effects.
KeywordsAcid sphingomyelinase Functional inhibitors of ASM activity (FIASMAs) Imipramine Desipramine Fluoxetine Phospholipidosis Major depression
We thank Michaela Henkel and Alice Konrad for excellent technical assistance. We are grateful to Lydia Pettermann and Heike Thomas for generating the chemical compounds. We thank Christiane Mühle for helpful comments on the manuscript and preparation of Fig. 3. This work was supported by funding from the Forschungsstiftung Medizin at the University Hospital Erlangen, the German Federal Ministry of Education and Research (BMBF, 01 EE1401C, to J. K.), and DFG grants KO 947/13-1 and GU 335/29-1 (to J.K. and E.G.).
PT and JK conceived and designed the experiments; PT and SL designed and performed the experiments and wrote parts of the paper; CR, JK and EG analyzed the data; SL, PG and JK contributed reagents/study materials/analysis tools; CR and PT wrote the paper. All authors read the paper and provided intellectual input.
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Conflict of interest
The authors declare no conflict of interest.