KETANSERIN ANALOGS - THE EFFECT OF STRUCTURAL MODIFICATION ON 5-HT2 SEROTONIN RECEPTOR-BINDING

Ketanserin (1) is a fairly selective 5-HT2 antagonist that binds both at 5-HT2A and 5-HT2C receptors. A previous structure-affinity relation ship study revealed that the structure of the piperidine-containing ke tanserin molecule could be rather severely abbreviated with little eff ect on 5-HT2A affinity. The present investigation explores several inc onsistencies identified in the earlier study and suggests that multipl e modes of binding may be possible for ketanserin analogues. Perhaps t he nature of the benzylic substituent is the most significant determin ant of the manner in which these agents bind at 5-HT2A receptors, and it is possible that certain orientations may avail themselves of an au xiliary binding site. Depending upon the length of the piperidine N-al kyl chain, variation of the benzylic substituent from a carbonyl, to a n alcohol, to a methylene group has a nonparallel influence on binding , and this may be further affected by the presence of a second ring ni trogen atom. The results of the present investigation provide evidence that although the structure of ketanserin can be abbreviated, and eve n modified by conversion of the piperidine ring to a piperazine, the r esultant analogues may bind in more than one orientation at the recept ors. A key structural feature that may play a prominent role in anchor ing or orienting these compounds at 5-HT2A receptors is the benzylic c arbonyl group