Ketanserin Analogues: Structure-Affinity Relationships for 5-HT2 and 5-HT1C Serotonin Receptor Binding

Article abstract of DOI:10.1021/jm00104a017

Ketanserin is the prototypic 5-HT₂ serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships.Furthermore, ketanserin also binds at 5-HT_1C receptors and even less is known about the influence of its structural features on 5-HT_1C receptor affinity.The present study reveals that the fluoro and carbonyl groups of the 4-fluorobenzoyl portion of ketanserin make small contributions to 5-HT₂ binding and that the intact benzoylpiperidine moiety is an important feature.Ring opening of the piperidine ring reduces affinity.Although the quinazoline-2,4-dione moiety also contributes to binding, it appears to play a smaller role and can be structurally simplified with retention of 5-HT₂ affinity.N-(4-Phenylbutyl)-4-(4-fluorobenzoyl)piperidine (39), for example, binds with nearly tha same affinity (K_i=5.3 nM) as ketanserin (K_i=3.5 nM).All of the compounds examined bind at 5-HT_1C sites with lower affinity than ketanserin, and some of the simplified analogues bind with nearly 10 times the 5-HT₂ versus 5-HT_1C selectivity of ketanserin; however, none displays > 120 fold selectivity.Several of the compounds, such as the amide 32 and the urea 33 represent examples of new structural classes of 5-HT₂ ligands.