Optimisation of in silico derived 2-aminobenzimidazole hits as unprecedented selective kappa opioid receptor agonists.

Abstract

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.

• Authors: Pradip K Sasmal, C Vamsee Krishna, S Sudheerkumar Adabala, M Roshaiah, Khaji Abdul Rawoof, Emima Thadi, K Pavan Sukumar, Srisailam Cheera, Chandrasekhar Abbineni, K V L Narasimha Rao, A Prasanthi, Kamal Nijhawan, Mahaboobi Jaleel, Lakshmi Ramachandran Iyer, T Krishna Chaitanya, Nirbhay Kumar Tiwari, N Lavanya Krishna, Vijay Potluri, Ish Khanna, Thomas M Frimurer, Michael Lückmann, Øystein Rist, Lisbeth Elster, Thomas Högberg
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 4 Pg. 887-92 (Feb 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 25599839 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Benzimidazoles
• Receptors, Opioid, kappa
• 2-aminobenzimidazole

Topics

• Amino Acid Sequence
• Benzimidazoles (pharmacology)
• Computer Simulation
• Humans
• Molecular Sequence Data
• Receptors, Opioid, kappa (agonists, chemistry)
• Sequence Homology, Amino Acid
• Structure-Activity Relationship