Optimization of a pharmacophore model for 5-HT4 agonists using CoMFA and receptor based alignment
Twenty two 5-HT4 agonists obtained from our laboratory and the recent literature were used to develop a CoMFA model to predict 5-HT4 agonist activity. Two models were produced and compared for predictivity, the first by alignments ba
Iskander, Magdy N.,Leung, Lok M.,Buley, Trevor,Ayad, Fadi,Di Iulio, Juliana,Tan, Yean Y.,Coupar, Ian M.
Synthesis, testing and structure-activity studies on a library of 5-HT 4 ligands
Several indole derivatives and analogues comprising a range of related structural classes were designed, synthesized and tested as ligands for the 5-HT4 receptor. Within each series, binding experiments showed compounds with good affinity demonstrating high percentage displacement values at 1 μM. The most potent of these (20) had a pKi of 8.54 demonstrating very good affinity. These indole analogues were combined with 55 ligands that were previously produced in our laboratory to explore the structure-activity relationships of these 5-HT4 ligands. A CoMFA (Comparative Molecular Field Analysis) analysis was used to extend an earlier simple pharmacophore to suggest two new molecular features beyond the primary amino binding site. The pharmacophore confirmed that a newly described tetrahydroquinoline analogue was able to match the basic requirements of the model and the pharmacology of this molecule is provided in more detail.
Hanna-Elias, Amir,Manallack, David T.,Levit, Alla,Nguyen, William,Ayad, Fadi,Perera, Glen,Shapiro, Marina,Irving, Helen R.,Coupar, Ian M.,Iskander, Magdy N.
experimental part
p. 344 - 354
(2012/05/19)
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