Abstract
MH.MZ, MDL 100907, and altanserin are structurally similar 4-benzoyl-piperidine derivatives and are well accommodated to receptor interaction models. We combined structural elements of different high-affinity and selective 5-HT(2A) antagonists, as MH.MZ, altanserin, and SR 46349B, to improve the binding properties of new compounds. Three new derivatives were synthesized with a 4-benzoyl-piperidine moiety as the lead structure. The in vitro affinity of the novel compounds was determined by a [³H]MDL 100907 competition binding assay. The combination of MH.MZ and SR 46349B resulted in a compound (8) with a moderate affinity toward the 5-HT(2A) receptor (K(i) = 57 nm). The remarkably reduced affinity of other compounds (4a), (4b), and (4c) (K(i) = 411, 360 and 356 nm respectively) indicates that MH.MZ can only bind to the 5-HT(2A) receptor with the p-fluorophenylethyl residue in a sterically restricted hydrophobic binding pocket.
| Original language | English |
|---|---|
| Journal | Chemical Biology & Drug Design |
| Volume | 76 |
| Issue number | 4 |
| Pages (from-to) | 361-366 |
| ISSN | 1747-0277 |
| DOIs | |
| Publication status | Published - Oct 2010 |
| Externally published | Yes |
Bibliographical note
© 2010 John Wiley & Sons A/S.Keywords
- Binding, Competitive
- Combinatorial Chemistry Techniques
- Fluorobenzenes/chemistry
- Hydrophobic and Hydrophilic Interactions
- Ketanserin/analogs & derivatives
- Ligands
- Phenols/chemistry
- Piperidines/chemistry
- Protein Binding
- Pyridines/chemistry
- Receptor, Serotonin, 5-HT2A/chemistry
- Serotonin 5-HT2 Receptor Antagonists/chemistry