Chem Biol Drug Des. 2010 Oct;76(4):361-6. doi: 10.1111/j.1747-0285.2010.01011.x. Epub 2010 Jul 15.
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.
MH.MZ、MDL 100907 和阿坦色林是结构相似的 4-苯甲酰基哌啶衍生物，它们很好地适应了受体相互作用模型。我们结合了不同高亲和力和选择性 5-HT(2A)拮抗剂的结构元素，如 MH.MZ、阿坦色林和 SR 46349B，以改善新化合物的结合性能。我们用 4-苯甲酰基哌啶部分作为先导结构合成了三个新的衍生物。新型化合物的体外亲和力通过 [³H]MDL 100907 竞争结合测定来确定。MH.MZ 和 SR 46349B 的结合导致一种化合物（8）对 5-HT(2A)受体具有中等亲和力（K(i) = 57nm）。其他化合物（4a）、（4b）和（4c）的亲和力显著降低（K(i) = 411、360 和 356nm 分别）表明，MH.MZ 只能与 5-HT(2A)受体结合，其苯环上的氟乙基取代基在空间受限的疏水性结合口袋中。
