Dihydrobenzofuran analogues of hallucinogens .4. Mescaline derivatives
Dihydrobenzofuran analogues of hallucinogens .4. Mescaline derivatives
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DOI：
10.1021/jm970219x
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发表时间：
1997-09-12
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;Waldman, SR;Nichols, DE
二氢苯并呋喃和四氢苯并二呋喃官能团被用作原型致幻剂mescaline（1）中芳香甲氧基的构象限制生物电子等排体。因此，制备了4-（2-氨基乙基）-6，7-二甲氧基-2，3-二氢苯并呋喃盐酸盐（8）和1-（8-甲氧基-2，3，5，6-四氢苯并[1，2-B：5，4-b ′]二呋喃-4-基）-2-氨基乙烷盐酸盐（9），并与1一起沿着评价了在训练用于区分盐水和酒石酸LSD（0.08 mg/kg）的大鼠中的双杠杆药物辨别（DD）范例中的活性。此外，测定了1、8和9从大鼠皮质匀浆5-HT 2A受体中置换[H-3]酮色林和从大鼠海马匀浆5-HT 1A受体中置换[H-3]8-OH-DPAT的能力。此外，评价了这些化合物竞争激动剂和拮抗剂与表达克隆的人5-HT 2A、5-HT 2B和5-HT 2C受体的细胞结合的能力。最后，通过测量表达大鼠5-HT 2A或5-HT 2C受体的NIH 3 T3细胞中的磷酸肌醇水解来评估激动剂功效。尽管在DD试验中1完全替代了LSD（ED 50 = 33.5 μ mol/kg），但8和9都不能替代LSD，只有50%的大鼠给药8选择药物水平，只有29%的大鼠给药9选择药物水平。所有测试化合物对大鼠脑匀浆中的5-HT 1A和5-HT 2A受体具有微摩尔亲和力。奇怪的是，化合物在5-HT 2A位点的亲和力的等级顺序与它们在行为测定中的效力顺序相反。对刺激磷酸肌醇周转的能力作为功能功效的量度的评价显示，所有化合物在5-HT 2C受体中具有与5-羟色胺大致相等的功效。然而，在5-HT 2A受体，8和9的有效性明显较低，分别仅引起最大反应的61%和45%。这些结果与苯乙胺类致幻剂的作用机制一致，即此类化合物必须是5-HT 2A受体亚型的完全激动剂。与2，5-二甲氧基取代的苯乙胺相反，其中甲氧基的刚性化对活性没有有害影响，3，4，5-三氧化的美斯卡灵类似物的活性损失可能表明3和5甲氧基必须保持构象移动的以使受体活化。
Dihydrobenzofuran and tetrahydrobenzodifuran functionalities were employed as conformationally restricted bioisosteres of the aromatic methoxy groups in the prototypical hallucinogen, mescaline (1). Thus, 4-(2-aminoethyl)-6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride (8) and 1-(8-methoxy-2,3,5,6-tetrahydrobenzo[1,2-b:5,4-b']difuran-4-yl)-2-amimoethane hydrochloride (9) were prepared and evaluated along with 1 for activity in the two-lever drug discrimination (DD) paradigm in rats trained to discriminate saline from LSD tartrate (0.08 mg/kg). Also, 1, 8, and 9 were assayed for their ability to displace [H-3]ketanserin from rat cortical homogenate 5-HT2A receptors and [H-3]8-OH-DPAT from rat hippocampal homogenate 5-HT1A receptors. In addition, these compounds were evaluated for their ability to compete for agonist and antagonist binding to cells expressing cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Finally, agonist efficacy was assessed by measurement of phosphoinositide hydrolysis in NIH 3T3 cells expressing the rat 5-HT2A or 5-HT2C receptors. Although 1 fully substituted for LSD in the DD assays (ED50 = 33.5 mu mol/kg), neither 8 nor 9 substituted for LSD, with just 50% of the rats, administered 8 selecting the drug lever, and only 29% of the rats administered 9 selecting the drug lever. All of the test compounds had micromolar affinity for the 5-HT1A and 5-HT2A receptors in rat brain homogenate. Curiously, the rank order of affinities of the compounds at 5-HT2A sites was opposite their order of potency in the behavioral assay. An evaluation for ability to stimulate phosphoinositide turnover as a measure of functional efficacy revealed that all the compounds were of approximately equal efficacy to serotonin in 5-HT2C receptors. At 5-HT2A receptors, however, 8 and 9 were significantly less efficacious, eliciting only 61 and 45%, respectively, of the maximal response. These results are consistent with the proposed mechanism of action for phenethylamine hallucinogens, that such-compounds must be full agonists at the 5-HT2A receptor subtype. In contrast to the 2,5-dimethoxy-substituted phenethylamines, where rigidification of the methoxy groups had no deleterious effect on activity, the loss of activity in the 3,4,5-trioxygenated mescaline analogues may suggest that the 3 and 5 methoxy groups must remain conformationally mobile to enable-receptor activation.