Identification of New Functional Inhibitors of Acid Sphingomyelinase Using a Structure−Property−Activity Relation Model

Abstract

Some organic weak bases induce a detachment from inner lysosomal membranes and subsequent inactivation of acid sphingomyelinase (ASM) and thus work as functional ASM inhibitors. The aim of the present investigation was to develop a structure-property-activity relation (SPAR) model in order to specify the structural and physicochemical characteristics of probes capable of functionally inhibiting ASM. High p K a and high log P values are necessary but not sufficient preconditions for functional inhibition of ASM. The experimental data supported the requirement of an additional factor, which is necessary for functional inhibition of ASM. This factor k is related to the steric hindrance of the most basic nitrogen atom and presumably modulates the free presentation of a protonated nitrogen atom at the inner lysosomal surface. During the course of the study, we characterized 26 new functional ASM inhibitors, including doxepine 63, fluoxetine 104, maprotiline 109, nortriptyline 114, paroxetine 118, sertraline 124, suloctidil 125, and terfenadine 127.

Acid sphingomyelinase–ceramide system mediates effects of antidepressant drugs

“…1b,c; Supplementary Fig. 1a,b,d, Supplementary note 1), a finding consistent with the induction of partial proteolysis of Asm by amitriptyline and fluoxetine 15,16 . Mice transgenic for Asm (tAsm) exhibited increased Asm activity and protein levels in the hippocampus, and amitriptyline and fluoxetine reduced Asm activity and protein levels ( Fig.…”

“…To further substantiate the role of the Asm/ceramide system as a target for antidepressants, we tested whether fendiline, a functional inhibitor of ASM 16 , that has not been reported to be an antidepressant, also acts as antidepressant. Fendiline reduced Asm activity and reduced ceramide concentrations in the hippocampus in WT and t-Asm ( Fig.…”

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

“…Several studies [77-80] identified pharmacological inhibitors of the acid sphingomyelinase; the acid sphingomyelinase seems to interact with intra-lysosomal membranes, thereby being protected against proteolytic inactivation [77]. Weak bases such as amitriptyline diffuse into cells, are protonated in lysosomes and concentrated in these organelles.…”

“…Weak bases such as amitriptyline diffuse into cells, are protonated in lysosomes and concentrated in these organelles. High pKa- and high logP-values of the drugs are necessary but not sufficient to functionally inhibit the acid sphingomyelinase [80]. These drugs interfere with binding of the acid sphingomyelinase to the membrane, which results in a detachment of the acid sphingomyelinase and subsequent proteolytic degradation [77-80].…”

“…High pKa- and high logP-values of the drugs are necessary but not sufficient to functionally inhibit the acid sphingomyelinase [80]. These drugs interfere with binding of the acid sphingomyelinase to the membrane, which results in a detachment of the acid sphingomyelinase and subsequent proteolytic degradation [77-80]. The lipophilic ring structures that are present in all acid sphingomyelinase inhibitors are embedded in the lysosomal membrane, while the cationic amino group linked through an aliphatic chain to the ring system of all acid sphingomyelinase inhibitors interferes with binding of the enzyme to the membrane finally resulting in detachment and subsequent proteolytic degradation in the lysosome [80].…”