Dihydrobenzofuran analogues of hallucinogens .3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups
Dihydrobenzofuran analogues of hallucinogens .3. Models of 4-substituted (2,5-dimethoxyphenyl)alkylamine derivatives with rigidified methoxy groups
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DOI：
10.1021/jm960199j
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发表时间：
1996-07-19
影响因子：
7.3
通讯作者：
Nichols, DE
中科院分区：
文献类型：
--
作者：
Monte, AP;MaronaLewicka, D;Nichols, DE
四氢苯并二呋喃功能被用作构象限制的生物电子等排体的芳族甲氧基在原型致幻苯烷基胺1和2。因此，制备了一系列8-取代的1-（2，3，6，7-四氢苯并[1，2-B：4，5-b ′]二呋喃-4-基）-2-氨基烷烃（7 a-e），并评价了在训练用于区分生理盐水和酒石酸LSD（0.08 mg/kg）的大鼠中的双杠杆药物辨别范例中的活性，以及从大鼠皮质匀浆5-HT 2 A受体中置换[H-3]酮色林和从大鼠海马匀浆5-HT 1 A受体中置换[（3）H-3 -8-OH-DPAT的能力。此外，评价了1-（8-（溴-2，3，6，7-四氢苯并[1，2-B：4，5-（7 B）），其在大鼠体内试验中被发现非常有效，其与[I-125][DOI]和[H-3]酮色林竞争结合表达克隆人5-HT 2 A、5-H-2 B和5-HT 2 C受体的细胞的能力。在烷基胺侧链对位具有疏水取代帕拉的所有二氢呋喃基化合物在体外和体内测定中具有等于或超过类似构象柔性母体化合物的活性的活性。例如，7 b在药物辨别测定中取代LSD，其艾德（50）为61 nmol/kg，并且对于从大鼠和人5-HT 2受体置换放射性配体具有纳摩尔至亚纳摩尔范围的Ki值，使其成为迄今报道的最有效的致幻剂样苯基烷基胺衍生物之一。结果表明，这些pew类似物中的二氢呋喃环有效地模拟了母体化合物1和2的甲氧基的活性结合构象。此外，结果提供了有关的地形和相对取向的残基参与激动剂结合在5-羟色胺5-HT 2受体。
Tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in prototypical hallucinogenic phenylalkylamines 1 and 2. Thus, a series of 8-substituted 1-(2,3,6,7-tetrahydrobenzo[ 1,2-b:4,5-b']difuran-4-yl)-2-aminoalkanes (7a-e) were prepared and evaluated for activity in the two-lever drug discrimination paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg) and for the ability to displace [H-3]ketanserin from rat cortical homogenate 5-HT2A receptors and [(3)H3-8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, 1-(8-(bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5- (7b), which was found to be extremely potent in the rat in vivo assays, was evaluated for its ability to compete with [I-125][DOI and [H-3]ketanserin binding to cells expressing cloned human 5-HT2A, 5-H-2B, and 5-HT2C receptors. All of the dihydrofuranyl compounds having a hydrophobic substituent para to the alkylamine side chain had activities in both the in vitro and in vivo assays that equaled or surpassed the activity of the analogous conformationally flexible parent compounds. For example, 7b substituted for LSD in the drug discrimination assay with an ED(50) Of 61 nmol/kg and had K-i values in the nanomolar to subnanomolar range for the displacement of radioligand from rat and human 5-HT2 receptors, making it one of the most potent hallucinogen-like phenylalkylamine derivatives reported to date. The results suggest that the dihydrofuran rings in these pew analogues effectively model the active binding conformations of the methoxy groups of the parent compounds 1 and 2. In addition, the results provide information about the topography and relative orientation of residues involved in agonist binding in the serotonin 5-HT2 receptors.