Structural modifications to an N-methyl-D-aspartate receptor antagonist result in large differences in trapping block.
Bibliographic record
Abstract
Differences in the degree of trapping of initial block by N-methyl-D-aspartate (NMDA) receptor antagonists may affect their safety and, hence, suitability for clinical trials. In this comparative study, 23 compounds structurally related to the low-affinity, use-dependent NMDA receptor antagonist (S)-alpha-phenyl-2-pyridineethanamine dihydrochloride (AR-R15896AR) were examined to determine the degree of trapping block they exhibit. Compounds were tested at concentrations that produced a comparable initial 80% block of NMDA-mediated whole-cell current in rat cortical cultures. A wide range of values of trapping block was found, indicating that trapping is not an all-or-none event. Fifteen of the compounds trapped significantly more than the 54 +/- 3% of initial block trapped by AR-R15896AR. The off-rates of these compounds were slower than that of AR-R15896AR. Only 2 of the 23 compounds trapped significantly less than AR-R15896AR. AR-R15808, the piperidine analog of AR-R15896AR, appeared to trap only 8 +/- 3% of its initial block, although its fast off-rate confounded accurate quantification of trapping. AR-R26952, which, like AR-R15896AR, contains a pyridine in place of a phenyl group, trapped 40 +/- 5% of its initial block and exhibited kinetics comparable with AR-R15896AR. Structure-activity analysis suggested that the presence of two basic nitrogen atoms and decreased hydrophobicity led to decreased trapping. There was no correlation between trapping and lipophilicity as would be expected if closed-channel egress was due to escape through the lipid bilayer. However, there was a positive correlation between off-rate and degree of trapping. Models that can account for partial trapping are presented.
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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".