Abstract
The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.
Highlights
Drug repurposing is a novel research topic as a substitute to underperforming hypothesisdriven molecular target-based drug discovery efforts [1]
The current study aimed to investigate whether the crossing ability of OMR for the blood–brain barrier (BBB) will be enhanced after the multiple dose for 28 days and to assess if the developed LC-MS/MS method is valid for the bioassay of OMR in the actual biological samples
Where is the study aiming to find out whether OMR after passing BBB would achieve central anti Parkinson activity or not, OMR was docked into the crystal structures of the A2A adenosine receptor (A2AAR) that is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release
Summary
Drug repurposing is a novel research topic as a substitute to underperforming hypothesisdriven molecular target-based drug discovery efforts [1]. Omarigliptin (OMR) is a novel once weekly anti-diabetic drug [6]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are well-known effective potential agents against type 2 diabetes mellitus (DM). Unlike the classical once-daily DPP-4 inhibitors, once-weekly administration could boost the patients’ compliance [18]. This will depict a major outcome if the drug had been repositioned successfully for Parkinson’s disease (PD) or at least as a neuroprotective agent against other neurodegenerative diseases. Repositioning of a once-weekly anti-diabetic drug for the management of PD will promote the patient’s adherence with potential financial privilege due to onceweekly dosing regimen. The potential neuroprotective effect of GLP-1 had been previously reported owing to the promising antiparkinsonian effect of DPP-4 inhibitors (Gliptins, anti-diabetics) [20,21]. Drug repurposing is an uprising revolution of drug discovery that presents major and prominent privilege with already approved safer agents by scanning the current candidates
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