The <i>In Vivo</i> Effects of the CB <sub>1</sub> -Positive Allosteric Modulator GAT229 on Intraocular Pressure in Ocular Normotensive and Hypertensive Mice
Bibliographic record
Abstract
Purpose: Orthosteric cannabinoid receptor 1 (CB1) activation leads to decreases in intraocular pressure (IOP). However, use of orthosteric CB1 agonists chronically has several disadvantages, limiting their usefulness as clinically relevant drugs. Allosteric modulators interact with topographically distinct sites to orthosteric ligands and may be useful to circumvent some of these disadvantages. The purpose of this study was to investigate the effects of the novel CB1-positive allosteric modulator (PAM) GAT229 on IOP. Methods: IOP was measured using rebound tonometry in anesthetized normotensive C57Bl/6 mice and in a genetic model of ocular hypertension [nose, eyes, ears (nee) mice] before drug administration, and at 1, 6, and 12 h thereafter. Results: In normotensive mice, topical administration of 5 μL GAT229 alone at either 0.2% or 2% did not reduce IOP. However, a subthreshold dose (0.25%) of the nonselective orthosteric CB1 agonist WIN 55,212-2, when combined with 0.2% GAT229, significantly reduced IOP compared with vehicle at 6 and 12 h. Similarly, combination of subthreshold Δ9-tetrahydrocannabinol (a nonselective orthosteric CB1 agonist; 1 mg/kg) with topical 0.2% GAT229 produced IOP lowering at 6 h. In nee mice, administration of topical 0.2% GAT229 or 10 mg/kg GAT229 alone was sufficient to lower IOP at 6 and 12 h, and 12 h, respectively. Conclusions: The CB1 PAM GAT229 reduces IOP in ocular hypertensive mice and enhanced CB1-mediated IOP reduction when combined with subthreshold CB1 orthosteric ligands in normotensive mice. Administration of CB1 PAMs may provide a novel approach to reduce IOP with fewer of the disadvantages associated with orthosteric CB1 activation.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".