Analogues of the dioxolanes dexoxadrol and etoxadrol as potential phencyclidine-like agents. Synthesis and structure-activity relationships.
Analogues of the dioxolanes dexoxadrol and etoxadrol as potential phencyclidine-like agents. Synthesis and structure-activity relationships.
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二氧戊环 dexoxadrol 和 etoxadrol 的类似物作为潜在的苯环己哌啶类药物。
DOI：
10.1021/jm00086a001
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发表时间：
1992
影响因子：
7.3
通讯作者：
Monn,JA
中科院分区：
文献类型：
--
作者：
Thurkauf,A;Mattson,MV;Richardson,S;Mirsadeghi,S;Ornstein,PL;HarrisonJr,EA;Rice,KC;Jacobson,AE;Monn,JA
合成了一系列基于二氧杂环己烷((4S，6S)-2，2-二苯基-4-(2-哌啶基)-L，3-二氧戊环)和埃托沙德罗((2S，4S，6S)-2-乙基-2-苯基-4-(2-哌啶基)-L，3-二氧戊环)的二氧杂环戊烷类似物，并测试了它们取代大鼠脑组织匀浆中五氯酚(L-(L-苯基环己基)哌啶)结合部位的能力。通过修饰分子的三个主要结构单元地塞克沙德罗、哌啶、1，3-二氧杂环戊烷和芳香环，探索了该系列的定性构效关系。地塞克沙德罗的N-烷基衍生物被发现是无效的，正如那些二氧杂环戊环被修饰的类似物一样。比较了苯基取代的etoxadrol类似物和类似取代的PCP类似物，发现它们的构效关系存在明显的差异，表明这两类药物中的芳环与PCP结合部位的作用是不同的。用2-或3-噻吩环取代埃托沙德罗中的苯环，得到与埃托沙德罗相似的亲和力的化合物，用丙基(7)或异丙基(8)取代埃托沙德罗的二氧戊环上的乙基部分，得到比埃托沙德罗或PCP更有效的化合物。最有效的化合物是(2S，4S，6S)-2-ethyl-2-(l-chlorophenyl)-4-(2-piperidyl)-l，)3-二氧杂环戊烷(11)，其中氯部分被放置在etoxadrol芳环的邻位位置。其体外效价与磷酸三钙相当。
A series of dioxolane analogues based on dexoxadrol ((4S, 6S)-2, 2-diphenyl-4-(2-piperidyl)-l, 3-dioxolane) and etoxadrol ((2S, 4S, 6S)-2-ethyl-2-phenyl-4-(2-piperidyl)-l, 3-dioxolane) were prepared and tested fortheir ability to displace [3H] TCP (1-[1-(2-thienyl) cyclohexyl] piperidine) from PCP (l-(l-phenylcyclohexyl) piperidine) binding sites in rat brain tissue homogenates. Qualitative structure-activity relationships within this series were explored through modifications of the three major structural units of dexoxadrol, the piperidine, 1, 3-dioxolane, and aromatic rings of the molecule. N-Alkyl derivatives of dexoxadrol were found to be inactive, as were those analogues where the dioxolane ring was modified. Phenyl-substituted etoxadrol analogues were compared to similarly substituted PCP analogues and distinct differences were found in their structure-activity relationships suggesting that the aromatic rings in these two drug classes interact differently with the PCP binding sites. The replacement of the phenyl ring in etoxadrol by either a 2-or 3-thienyl ring led to compounds with affinity comparable to etoxadrol, and the replacement of the ethyl moiety on etoxadrol’s dioxolane ringwith propyl (7) or isopropyl (8) led to compounds which were more potent than etoxadrol or PCP. The most potent compound was(2S, 4S, 6S)-2-ethyl-2-(l-chlorophenyl)-4-(2-piperidyl)-l, 3-dioxolane (11), where a chlorine moiety was placed in the ortho position in the aromatic ring of etoxadrol. Its potency was comparable with TCP in vitro.