Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS

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.

Sodium-glucose cotransporter 2 inhibitors and neurological disorders: a scoping review

“… 33 Their antagonists have been proven to decrease off-time and troublesome dyskinesia while offering neuroprotection. 34 Ayoub et al 35 examined this target in their docking study, revealing a stable complex formation between A2AAR and SGLT2i. Therefore, SGLT2i may be an effective antagonist against the A2AAR, although it may be intriguing to compare its docking energy to known antagonists such as istradefylline.…”

Liraglutide attenuate central nervous inflammation and demyelination through AMPK and pyroptosis‐related NLRP3 pathway

“…Not only clinical trials but also animal experiments indicate GLP‐1R agonists could improve neurodegenerative diseases, such as Parkinson's disease 13,14 and Alzheimer's disease, 15,16 while GLP‐1R also exerts therapeutic efficacy on brain ischemia, 17,18 traumatic brain injury, 19 and psychiatric disorders 20–22 in animal models. Besides, various kinds of DPP‐4 inhibitors, which can increase the level of endogenous GLP‐1 level, exhibit neuroprotective and cognitive protective effects either 23–25 …”

“…Besides, various kinds of DPP‐4 inhibitors, which can increase the level of endogenous GLP‐1 level, exhibit neuroprotective and cognitive protective effects either. 23 , 24 , 25 …”

Drug Repositioning For Allosteric Modulation of VIP and PACAP Receptors

“…Other examples of successful library screens against GPCRs are: fenoprofen – a COX-2 inhibitor, identified as a new positive allosteric modulator of melanocortin receptor 3 ( 26 ), and lorazepam – a modulator of GPR68, proposed as a new therapeutic for pancreatic cancer ( 27 ). A more recent example proposed by docking is omarigliptin, DPP-4 inhibitor, repurposed for A 2A receptor ( 28 ). A different approach to drug repurposing based on virtual screening provided new inhibitors of the PAR-2 receptor ( 29 ) by selecting at first 150 hits, out of which 8 compounds were further selected to be tested in bioassays and 4 compounds finally demonstrated an inhibitory effect.…”