We report on the design, synthesis, and structure activity relationship studies of novel Org 27569 analogues as potential allosteric modulators of the CB1 receptors. We also investigated by computer modelling the possible location of the allosteric site on CB1 and the binding confirmation of the allosteric ligands. Docking of the synthesised molecules is also performed and the results are compared to the results of the biological bioassays. The synthesis of non-fused indole analogues of Org 27569 is described. These analogues were systematically varied to study the importance of key functional groups for CB1 allosteric activity. It was found that the two NH groups of the indole derivatives are required for activity. Activity is also significantly improved for analogues possessing a hydroxymethyl group or a hydrophobic chain at position 3 of the indole moiety. SAR analysis also shows that the presence of a dialkylamino group at the <i>para-</i>position on the aromatic side chain further improves the activity. Conformationally restricted analogues (fused indoles) of Org 27569 were prepared to determine the possible binding conformation of Org 27569.<i> </i>An analogue having the two NH groups directed in the same direction exhibited a moderate ability to enhance CP55,940 affinity and gave significant decrease in [<sup>35</sup>S]GTPγS binding at 1μM, indicating the possible binding conformation for the Organon derivatives. Molecular modelling studies allowed locating a possible binding pocket for the CB1 allosteric ligands. The study described here should help the design of ligands of the CB1 allosteric site that possess higher biological activities and specificities. The results should pave the way for the discovery of the anti-obesity drugs of the future.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:540507 |
| Date | January 2010 |
| Creators | Abdelrahman, Mostafa Hamed |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=159203 |
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