Indazole Inhibition of Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channels in Rat Epididymal Epithelial Cells1
Bibliographic record
Abstract
Previous studies have shown that two indazole compounds, lonidamine [1-(2,4-dichlorobenzyl)-indazole-3-carboxylic acid] and its analogue AF2785 [(1-(2,4-dichlorobenzyl)-indazol-3-acrylic acid], suppress fertility in male rats. We also found that these compounds inhibit the cystic fibrosis transmembrane conductance regulator chloride (CFTR-Cl(-)) current in epididymal epithelial cells. To further investigate how lonidamine and AF2785 inhibit the current, we used a spectral analysis protocol to study whole-cell CFTR current variance. Application of lonidamine or AF2785 to the extracellular membrane of rat epididymal epithelial cells introduced a new component to the whole-cell current variance. Spectral analysis of this variance suggested a block at a rate of 3.68 micro mol(-1)/sec(-1) and an off rate of 69.01 sec(-1) for lonidamine, and an on rate of 3.27 micro mol(-1)/sec(-1) and an off rate of 108 sec(-1) for AF2785. Single CFTR-Cl(-) channel activity using excised inside-out membrane patches from rat epididymal epithelial cells revealed that addition of lonidamine to the intracellular solution caused a flickery block (a reduction in channel-open time) at lower concentration (10 micro M) without any effect on open channel probability or single-channel current amplitude. At higher concentrations (50 and 100 micro M), lonidamine showed a flickery block and a decrease in open-channel probability. The flickery block by lonidamine was both voltage-dependent and concentration-dependent. These results suggest that lonidamine and AF2785, which are open-channel blockers of CFTR at low concentrations, also affect CFTR gating at high concentrations. We conclude that these indazole compounds provide new pharmacological tools for the investigation of CFTR. By virtue of their interference with reproductive processes, these drugs have the potential for being developed into novel male contraceptives.
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How this classification was reachedexpand
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| 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 | 0.000 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".