SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIP OF C5-SUBSTITUTED ANALOGS OF (+/-)-10,11-DIHYDRO-5H-DIBENZO[A,D]CYCLOHEPTEN-5,10-IMINE [(+/-)-DESMETHYL-MK801] - LIGANDS FOR THE NMDA RECEPTOR-COUPLED PHENCYCLIDINE BINDING-SITE
SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIP OF C5-SUBSTITUTED ANALOGS OF (+/-)-10,11-DIHYDRO-5H-DIBENZO[A,D]CYCLOHEPTEN-5,10-IMINE [(+/-)-DESMETHYL-MK801] - LIGANDS FOR THE NMDA RECEPTOR-COUPLED PHENCYCLIDINE BINDING-SITE
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DOI：
10.1021/jm00165a029
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发表时间：
1990-03-01
影响因子：
7.3
通讯作者：
RICE, KC
中科院分区：
文献类型：
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作者：
MONN, JA;THURKAUF, A;RICE, KC
一系列八个C5-取代的（. ±.）- 10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺（1）是通过其（±）- N-叔丁基甲脒基衍生物2，然后甲脒溶剂分解。通过精制C5-乙酯衍生物制备另外10种类似物。类似物处理大（如丙基和更大）亲脂性取代基取代[3H]-1-（1-噻吩基环己基）哌啶（[3H] TCP）从高亲和力苯环利定（PCP）结合位点在大鼠脑匀浆中仅在高浓度（Ki> 1000 nM）;然而，极性氨基官能团（如2-氨乙基）的存在抵消了这种效应（Ki = 20 nM）。因此，大于乙基的亲脂性取代基的边界条件似乎是极性的。1的11个相对小的（MR <14）C5取代的类似物与N-甲基-D-天冬氨酸（NMDA）受体相关的高亲和力PCP结合位点的相互作用最好用方程log（1/Ki）= 5.837 + 5.837 + 0.64 π描述。+ 7.41（r = 0.90）。
A series of eight C5-substituted analogues of (.+-.)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (.+-.)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaboration of the C5-ethylester derivative. Analogues processing large (e.g.propyl and larter) lipophilic substituents displace [3H]-1-(1-thienylcyclohexyl)piperidine ([3H]TCP) from the high-affinity phencyclidine (PCP) binding site in rat brain homogenates only at high concentratiosn (Ki > 1000 nM); however, the presence of a polar amino functionality (e.g. 2-aminoethyl) offsets this effect (Ki = 20 nM). Thus, the boundary conditions for lipophilic substituents larger than ethyl appears to be polar in nature. Interaction of the 11 relatively small (MR < 14) C5-substituted analogues of 1 with the high-affinity PCP binding site associated with the N-methyl-D-aspartate (NMDA) receptor is best described by the equation log (1/Ki) = 5.837 + 5.837 + 0.64.pi. + 7.41 (r = 0.90).