Cardioselectivity of the sulphonylurea HMR 1098: studies on native and recombinant cardiac and pancreatic K<sub>ATP</sub> channels
Bibliographic record
Abstract
In this study we investigated the effects of the putative cardioselective sulphonylurea derivative HMR 1098 on ATP-sensitive potassium (K(ATP)) channels from cardiac ventricular myocytes, the INS-1 beta-cell line and from recombinant K(ATP) channels composed of SUR2A/Kir6.2, SUR1/Kir6.2, SUR1/Kir6.1 an Kir6.2,DeltaC26. Recombinant channels were expressed in tsA201 or COS-1 cells. The effects of HMR 1098 on single channel and whole-cell currents were recorded using the patch-clamp technique. At the single channel level, using excised inside-out membrane patches, HMR 1098 inhibited K(ATP) channels from ventricular cells and INS-1 cells with IC(50)s of 0.88 and 720 microM respectively. Similar results to those in cardiac cells were obtained using recombinant SUR2A/Kir6.2 K(ATP) channels. HMR 1098 inhibition of SUR2A/Kir6.2 K(ATP) channels was unaffected by the presence of internal ADP. In whole-cell recordings, HMR 1098 inhibited SUR2A/Kir6.2 and SUR1/Kir6.2 currents with IC(50)s of 2.1 and 860 microM respectively. HMR 1098 was without effect on currents either from the Kir6.2,DeltaC26 truncation mutant or from Kir2.1. Our results demonstrate that HMR 1098 is a selective inhibitor of cardiac K(ATP) channels, showing a 400 - 800-fold selectivity over beta-cell K(ATP) channels. The non-aromatic substitutions in the sulphonylurea moiety greatly increase the cardioselectivity of this compound while reducing the overall blocking potency of this sulphonylurea derivative.
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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 | 0.000 |
| 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 | 0.000 |
| 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 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".