Oxatomide

Oxatomide, an antihistamine drug of the diphenylmethylpiperazine family, has anti‐inflammatory effects in airway disease. Because oxatomide was shown to cause diverse physiological responses in several cell models, the impact of oxatomide on Ca2+ signaling and its related physiological effects has not been explored in IMR‐90 human fetal lung fibroblasts.

This study assessed the effect of oxatomide on cell viability and intracellular free Ca2+ concentrations ([Ca2+]i) and examined whether oxatomide‐induced cytotoxicity through Ca2+ signaling in IMR‐90 cells.

Cell viability was measured by the cell proliferation reagent (WST‐1). [Ca2+]i was measured by the Ca2+‐sensitive fluorescent dye fura‐2.

Oxatomide (10–40 μM) concentration dependently reduced cell viability and induced [Ca2+]i rises in IMR‐90 cells. This cytotoxic effect was reversed by chelation of cytosolic Ca2+ with BAPTA‐AM. In terms of Ca2+ signaling, oxatomide‐caused Ca2+ entry was inhibited by modulators of store‐operated Ca2+ channels (2‐APB and SKF96365) and protein kinase C (PKC) inhibitor (GF109203X). Furthermore, oxatomide‐induced Ca2+ influx was confirmed by Mn2+‐induced quench of fura‐2 fluorescence. In a Ca2+‐free medium, preincubation with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin inhibited oxatomide‐evoked [Ca2+]i rises. Conversely, treatment with oxatomide abolished thapsigargin‐induced [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 also inhibited oxatomide‐caused [Ca2+]i rises.

In IMR‐90 cells, oxatomide‐induced cytotoxicity by preceding [Ca2+]i rises involving PKC‐sensitive store‐operated Ca2+ entry and PLC‐dependent Ca2+ release from the endoplasmic reticulum. BAPTA‐AM, with its Ca2+ chelating effects, may be a potential compound for preventing oxatomide‐induced cytotoxicity.

The OCNH unit is one of the most frequently encountered structural motifs in rings in drugs which serves dual role as the proton donor through NH bond and proton acceptor through the CO bond. Here, we predicted the HB strength (Eint) of OCNH motif with H2O for commonly observed 37 rings in drugs with DFT method M06L/6‐311++G(d,p). The HB strength is rationalized in terms of molecular electrostatic potential (MESP) topology parameters ΔVn(NH)and ΔVn(CO)which describe the relative electron deficient/rich nature of NH and CO, respectively, with respect to the reference formamide. TheEintof formamide is −10.0 kcal/mol whereas theEintof ring systems is in the range −8.6 to −12.7 kcal/mol—a minor increase/decrease compared to the formamide. The variations inEintare addressed using the MESP parameters ΔVn(NH)and ΔVn(CO)and proposed the hypothesis that a positive ΔVn(NH)enhances NH…Owinteraction while a negative ΔVn(CO)enhances the CO…Hwinteraction. The hypothesis is proved by expressingEintjointly as ΔVn(NH)and ΔVn(CO)and also verified for twenty FDA approved drugs. The predictedEintfor the drugs using ΔVn(NH)and ΔVn(CO)agreed well with the calculatedEint. The study confirms that even delicate variations in the electronic feature of a molecule can be quantified in terms of MESP parameters and they provide a priori prediction of the HB strength. The MESP topology analysis is recommended to understand the tunability of HB strength in drug motifs.