Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists
| Autor: | Michael Lückmann, Thomas Högberg, Ish Kumar Khanna, K. Pavan Sukumar, Lisbeth Elster, Lakshmi Ramachandran Iyer, Pradip Kumar Sasmal, Chandrasekhar Abbineni, Mahaboobi Jaleel, Khaji Abdul Rawoof, Vijay Potluri, Emima Thadi, Kamal Nijhawan, A. Prasanthi, C. Vamsee Krishna, Thomas M. Frimurer, Øystein Rist, Srisailam Cheera, T. Krishna Chaitanya, K. V. L. Narasimha Rao, S. Sudheerkumar Adabala, M. Roshaiah, N. Lavanya Krishna, Nirbhay Kumar Tiwari |
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| Rok vydání: | 2015 |
| Předmět: |
Benzimidazole
In silico Molecular Sequence Data Clinical Biochemistry Pharmaceutical Science Pharmacology Biochemistry κ-opioid receptor Structure-Activity Relationship chemistry.chemical_compound Mediator In vivo Drug Discovery medicine Humans Computer Simulation Amino Acid Sequence Receptor Molecular Biology Sequence Homology Amino Acid Chemistry Receptors Opioid kappa Organic Chemistry Opioid Molecular Medicine Benzimidazoles Pharmacophore medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:887-892 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2014.12.064 |
| Popis: | Kappa opioid receptor (KOR) is an important mediator of pain signaling and it is targeted for the treatment of various pains. Pharmacophore based mining of databases led to the identification of 2-aminobenzimidazole derivative as KOR agonists with selectivity over the other opioid receptors DOR and MOR. A short SAR exploration with the objective of identifying more polar and hence less brain penetrant agonists is described herewith. Modeling studies of the recently published structures of KOR, DOR and MOR are used to explain the receptor selectivity. The synthesis, biological evaluation and SAR of novel benzimidazole derivatives as KOR agonists are described. The in vivo proof of principle for anti-nociceptive effect with a lead compound from this series is exemplified. |
| Databáze: | OpenAIRE |
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