DESIGN AND SYNTHESIS OF 3-BENZYL-7-n-BUTYL-QUINOLIN-2(1H)-ONE DERIVATIVES AS NEW GPR55 RECEPTOR MODULATORS
Bibliographic record
Abstract
The GPR55 receptor appears to be a new potential drug target for the treatment of metabolic and neurodegenerative diseases, cancer, osteoporosis and neuropathic pain, even though further studies are required to clarify its role. Potent and selective ligands could therefore represent potential tool compounds to validate this receptor as a pharmacological target, as well as to encourage drug discovery in this field. However, to date, their design remains challenging, given the lack of information about the GPR55 3D structure, and the limited number of ligands reported in the literature, most of which are poorly selective. In addition, data on their pharmacological evaluation appear to be often controversial and strongly influenced by the functional assay performed as well as the cell line used. Based on 3-benzylcoumarin derivatives previously reported as GPR55 antagonists, a set of novel modulators with a 3-benzylquinolin-2(1H)-one scaffold has been recently developed in the research laboratory where I carried out my thesis work. These compounds resulted to be potent GPR55 agonists and displayed Ki values in the low nanomolar range. Furthermore, the 7-n-butyl-5-methoxy-3-(2-methoxybenzyl)-quinolin-2(1H)-one derivative exhibited complete selectivity over both CBRs. From a homology modelling study of GPR55, it emerged that the ortho-substitution on the 3-benzyl group might be not essential for the receptor interaction. My thesis work consisted in the synthesis of 3-benzyl-7-n-butyl-quinolin-2(1H)-one derivatives in which the benzyl ortho-substituent was removed, in order to assess its effective influence on the interaction within the GPR55 binding pocket and to deepen the preliminary structure-activity relationships (SAR) for this type of molecules. Biological tests to evaluate the GPR55-affinity, selectivity and functional activity of the newly synthesized compounds are currently ongoing at the University of Saskatchewan (Canada).
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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) | 0.000 | 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) | 0.002 | 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".