4-Aminoethylpiperazinyl aryl ketones with 5-HT₁A/5-HT₇ selectivity.
Copyright policy )4-Aminoethylpiperazinyl aryl ketones with 5-HT₁A/5-HT₇ selectivity.
The well-known 5-HT(1A)/5-HT(7) selectivity issue was tackled by a new series of 4-aminoethylpiperazinyl aryl ketones (1a-1l) specifically designed to distinguish the two hydrophobic sites centered at the anchoring salt bridge. The 4-aminoethylpiperazinyl aryl ketones showed a wide spectrum of activity and selectivity for the 5-HT receptors depending on the type of the hydrophobic groups attached at the aryl piperazinyl ketone scaffold. Docking study of the most active compounds against 5-HT(7)R and 5-HT(1A)R revealed that both receptors have two hydrophobic pockets around the anchoring salt bridge. These two binding sites are perpendicular to each other in 5-HT(7)R but parallel in 5-HT(1A)R, and this observation is well matched with the previous report which claimed that 5-HT(7)R affinity arises from bent conformation of the bound ligand whereas an extended one is best suited for 5-HT(1A)R selectivity. Also, as these pockets have different size and shape, inhibitory activity as well as selectivity of the 4-aminoethylpiperazinyl aryl ketones against 5-HT(7)R and 5-HT(1A)R seemed to be determined by combination of two hydrophobic substituents attached at both ends of the title compounds.
- Konkuk University Korea (Republic of)
Binding Sites, Ketones, Piperazines, Cell Line, Protein Structure, Tertiary, Structure-Activity Relationship, Drug Design, Receptors, Serotonin, Receptor, Serotonin, 5-HT1A, Humans, Computer Simulation, Serotonin Antagonists, Hydrophobic and Hydrophilic Interactions, Protein Binding
Binding Sites, Ketones, Piperazines, Cell Line, Protein Structure, Tertiary, Structure-Activity Relationship, Drug Design, Receptors, Serotonin, Receptor, Serotonin, 5-HT1A, Humans, Computer Simulation, Serotonin Antagonists, Hydrophobic and Hydrophilic Interactions, Protein Binding
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