Increased activity of CF3-derivatized levamisole at the ACC-2 receptor from the parasitic nematode Haemonchus contortus
Bibliographic record
Abstract
The acetylcholine-gated chloride channel (ACC) family in parasitic nematodes represents a promising target for anthelmintic drug development. Levamisole, a widely known and utilized cholinergic agonist, has been used for decades to address many types of parasitic infections by targeting nematode nicotinic acetylcholine receptors (nAChRs) in nematodes. In this study, we report the synthesis and pharmacological evaluation of eight levamisole derivatives, five of which are novel, on the H. contortus ACC-2 receptor. This includes a CF 3 -derivatized compound we have identified as compound 6 whose structure contains levamisole as a backbone with the addition of a 2-trifluoromethyl benzyl group. Electrophysiological assays revealed that compound 6 exhibited a five-fold increase in sensitivity (EC 50 20 μM) compared to levamisole (EC 50 100 μM), our parent compound, with an EC 50 comparable to that of acetylcholine (20 μM). Investigation of the in silico docking of compound 6 with H. contortus ACC-2 suggest that it interacts uniquely within the H. contortus ACC-2 binding pocket, which may contribute to its increased receptor sensitivity. These findings highlight the potential of structural modifications containing an electron-withdrawing group at the 2-position which can significantly enhance activity at the H. contortus ACC-2 receptor. This opens many avenues for the development of more effective treatments against parasitic nematodes, in an environment with increasing resistance.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 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".