Dataset Information

The role of EP₂ receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

ABSTRACT:

Background

A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP₂ receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. The present studies were intended to determine EP₂ receptor involvement in mediating the long-term ocular hypotensive activity of JV-GL1 by using mice genetically deficient in EP₂ receptors.

Methods

The protracted IOP reduction produced by JV-GL1 was investigated in C57BL/6J and EP₂ receptor knock-out mice (B6.129-Ptger2^tm1Brey /J; EP₂KO). Both ocular normotensive and steroid-induced ocular hypertensive (SI-OHT) mice were studied. IOP was measured tonometrically under general anaesthesia. Aqueous humour outflow facility was measured ex vivo using iPerfusion in normotensive C57BL/6J mouse eyes perfused with 100 nM de-esterified JV-GL1 and in SI-OHT C57BL/6J mouse eyes that had received topical JV-GL1 (0.01%) 3 days prior.

Results

Both the initial 1-day and the protracted multiday effects of JV-GL1 in the SI-OHT model for glaucoma were abolished by deletion of the gene encoding the EP₂ receptor. Thus, JV-GL1 did not lower IOP in SI-OHT EP₂KO mice, but in littermate SI-OHT EP₂WT control mice, JV-GL1 statistically significantly lowered IOP for 4-6 days.

Conclusions

Both the 1-day and the long-term effects of JV-GL1 on IOP are entirely EP₂ receptor dependent.

SUBMITTER: Bertrand JA

PROVIDER: S-EPMC8875279 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

The role of EP<sub>2</sub> receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

Bertrand Jacques A JA Woodward David F DF Sherwood Joseph M JM Wang Jenny W JW Overby Darryl R DR

The British journal of ophthalmology 20201125 11

<h4>Background</h4>A single application of JV-GL1 substantially lowers non-human primate intraocular pressure (IOP) for about a week, independent of dose. This highly protracted effect does not correlate with its ocular biodisposition or correlate with the once-daily dosing regimen for other prostanoid EP<sub>2</sub> receptor agonists such as trapenepag or omidenepag. The underlying pharmacological mechanism for the multiday extended activity of JV-GL1 is highly intriguing. The present studies w ...[more]

PMID: 33239414

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Project description:BackgroundThe EP4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E2 (PGE2). Novel selective EP4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP4 (rEP4) receptor has been used as a surrogate for the human EP4 (hEP4) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP.ResultsRank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC50 and radioligand binding Ki. We observed variations between rat and human EP4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor. Additionally, these models helped identify key interactions between the EP4 receptor and ligands including PGE2 and several known sub-type selective agonists while serving as a marked improvement over the previously reported models.ConclusionsThis work has generated a set of novel homology models of the rEP4 and hEP4 receptors. The homology models provide an improvement upon the previously reported model, largely due to improved solvation. The hEP4 docking scores correlates best with the cAMP activation data, where both data sets rank order Rivenprost>CAY10684 > PGE1 ≈ PGE2 > 11-deoxy-PGE1 ≈ 11-dexoy-PGE2 > 8-aza-11-deoxy-PGE1. This rank-ordering matches closely with the rEP4 receptor as well. Species-specific differences were noted for the weak agonists Sulprostone and Misoprostol, which appear to dock more readily within human receptor versus rat receptor.

Project description:PurposePhacoemulsification has been linked to lowered intraocular pressure (IOP) in patients with glaucoma, ocular hypertension, anatomic narrow angles, and in glaucoma suspects, but the magnitude of change has varied.DesignRetrospective cohort study.ParticipantsPatients with glaucoma treated from June 2010 through May 2015 who underwent phacoemulsification (surgical group) were matched to patients who did not (nonsurgical group) for age, gender, type of glaucoma, baseline IOP, and number and type of glaucoma medications.MethodsElectronic medical record information was used to compare the matched surgical and nonsurgical groups.Main outcome measuresChange in IOP, change in number of glaucoma medications, and likelihood of a glaucoma procedure within 36 months after phacoemulsification. Intraocular pressure measures were obtained from Goldmann applanation tonometry when available (45%), and otherwise with the iCare tonometer (iCare USA, Raleigh, NC), the Tono-Pen (Reichert Technologies, Depew, NY), noncontact tonometry, and pneumotonometry.ResultsAmong 16 169 matched pairs, average IOP after the index date was lower in the surgical than nonsurgical group throughout follow-up to 36 months. The difference was greatest during months 1 through 18, during which IOP increased by 0.22 mmHg from 16.49 mmHg in the average nonsurgical patient and decreased by 0.99 mmHg from 16.50 mmHg in the average surgical patient (difference in difference, 1.21 mmHg; 95% confidence interval [CI], 1.12-1.30 mmHg). The difference in difference was greatest for patients with ocular hypertension (2.00 mmHg) and for patients with preoperative IOP of 20 mmHg or more (2.46 mmHg). By 30 to 36 months, 5% (95% CI, 4%-6%) fewer surgical patients used an ophthalmic medication. In the surgical group, the odds of selective laser trabeculoplasty were reduced in patients with ocular hypertension (odds ratio [OR], 0.27; 95% CI, 0.10-0.74) or glaucoma suspects (OR, 0.31; 95% CI, 0.20-0.47), whereas the odds of glaucoma surgery were elevated in surgical patients with primary open-angle glaucoma (OR, 1.48; 95% CI, 1.08-2.01).ConclusionsThe association of phacoemulsification for cataract with IOP reduction was lower than in past referral-based studies. Surgeons should expect to reduce IOP approximately 1 to 2 mmHg with phacoemulsification in patients with preoperative IOP of less than 20 mmHg.

Dataset Information

The role of EP₂ receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

Background

Methods

Results

Conclusions

Publications

The role of EP<sub>2</sub> receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

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The role of EP2 receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

Background

Methods

Results

Conclusions

Publications

The role of EP<sub>2</sub> receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The role of EP₂ receptors in mediating the ultra-long-lasting intraocular pressure reduction by JV-GL1.