Chimeras Derived from a P2Y<sub>14</sub> Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation
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Bibliographic record
Abstract
Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y 14 receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2Y 14 R-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2Y 14 R binding, suggesting that an optimal affinity (IC 50, nM) in the piperidine series was achieved for triazolyl N -linked glucose conjugates having one ( 8a, MRS4872, 3.21) or two ( 7a, MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2Y 14 R affinity (IC 50, nM) was achieved with N -linked glycosides of fucose 10f (6.19) and lactose 10h (1.88), and C -linked glucose 11a (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2Y 14 R antagonists. Two glycoconjugates that lacked a piperidine moiety, N -linked glucose derivative 10a and the isomeric C -linked glucose derivative 11a, were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate 7a of intermediate linker length and corresponding glucuronide 7b (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2Y 14 R antagonists having substantial in vitro and in vivo activity.
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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 | 0.000 | 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