Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Abstract The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6‐oxo‐5,6‐dihydro‐4 H ‐benzo[ f ]pyrrolo[1,2‐ a ][1,4]diazepin‐9‐yl‐6‐phenylhexylcarbamate ( 5 h ) and 4‐oxo‐5,6‐dihydro‐4 H ‐benzo[ f ]pyrrolo[1,2‐ a ][1,4]diazepin‐9‐yl‐(6‐phenylhexyl)carbamate ( 5 i ) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB 1 R), were selected for further studies. Results of cell‐based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h , 5 i , and our reference compound 3 ([3‐(3‐carbamoylpyrrol‐1‐yl)phenyl] N ‐(5‐phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox‐sensitive transcription factor NF‐κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg −1 all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.
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.
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it