ArticleJournal of medicinal chemistry2013
The importance of hydrogen bonding and aromatic stacking to the affinity and efficacy of cannabinoid receptor CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528).
Article in Journal of medicinal chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 19 citations in OpenAlex.
- Discovery of Potent and Selective CB2 Agonists Utilizing a Function-Based Computational Screening Protocol.ACS chemical neuroscience · 2023Article
- Antagonization of OXInternational journal of molecular sciences · 2022Article
- Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CBMolecules (Basel, Switzerland) · 2021Review
- GPR6 Structural Insights: Homology Model Construction and Docking Studies.Molecules (Basel, Switzerland) · 2020Article
- Aromatic interactions at the ligand-protein interface: Implications for the development of docking scoring functions.Chemical biology & drug design · 2018Article
- Minireview: From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation.Molecular endocrinology (Baltimore, Md.) · 2015Review
- Modeling, molecular dynamics simulation, and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs.Journal of chemical information and modeling · 2014Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Despite the therapeutic promise of the subnanomolar affinity cannabinoid CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528, 1), little is known about its binding site interactions and no primary interaction site for 1 at CB2 has been identified. We report here the results of Glide docking studies in our cannabinoid CB2 inactive state model that were then tested via compound synthesis, binding, and functional assays. Our results show that the amide functional group of 1 is critical to its CB2 affinity and efficacy and that aromatic stacking interactions in the TMH5/6 aromatic cluster of CB2 are also important. Molecular modifications that increased the positive electrostatic potential in the region between the fenchyl and aromatic rings led to more efficacious compounds. This result is consistent with the EC-3 loop negatively charged amino acid, D275 (identified via Glide docking studies) acting as the primary interaction site for 1 and its analogues.
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Registered trials
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