Add time:08/09/2019         Source:sciencedirect.com

Molecular modelling of leukotriene CysLT1 receptor antagonists have suggested that in addition to the two binding sites for a lipophilic and an acidic group, the receptor has a ‘third pocket’ to accommodate ‘three-armed’ ligands such as montelukast 1. Based on the most rigid CysLT1 receptor antagonist 3'-[2-(2-quinolinyl)ethenyl]flavone-8-carboxylic acid 2, we have synthesised 3-and 5′-substituted flavone derivatives to probe this additional binding pocket. Introduction of large substituents, e.g. 2-quinolinylmethoxy, to the C5′ position of the flavone skeleton abolished the CysLT1 receptor affinity whereas the same modification at the C3 position yielded a potent CysLT1 antagonist. This observation implies that the third binding pocket of the receptor has considerable steric tolerance, probably corresponding to the substituents at C3 of the flavone skeleton. Further modification by introducing a C3 substituent containing a basic nitrogen resulted in compound 6g with potent H1 antihistaminic activity although the CysLT1 antagonistic activity was much reduced. Further study on the CysLT1 receptor recognition of three-armed antagonists may facilitate the design of more effective antiasthmatic agents, e.g. dual antagonists of histamine H1 and leukotriene CysLT1 receptors.

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