Synthesis, evaluation, and comparative molecular field analysis of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for histamine H1 receptors
Synthesis, evaluation, and comparative molecular field analysis of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for histamine H1 receptors
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DOI：
10.1021/jm980428x
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发表时间：
1999-08-12
影响因子：
7.3
通讯作者：
Wyrick, SD
中科院分区：
文献类型：
--
作者：
Bucholtz, EC;Brown, RL;Wyrick, SD
先前发现一系列1-苯基-3-氨基-1,2,3,4-四氢萘（1-苯基-3-氨基tetralins， PATs）通过与[H-3]-(-)-(1R, 3S)-反式-2- pat标记的结合位点相互作用，调节啮齿动物前脑酪氨酸羟化酶活性和多巴胺合成。最近，我们发现在大鼠和豚鼠大脑中，PATs还与[H-3]-甲锥体标记的H-1受体具有高亲和力结合。在这里，我们报道了额外的PAT类似物的合成和生物学评价，以确定这两个位点的结合差异。进一步的分子修饰涉及悬垂的苯环以及季胺化合物。对38种PAT类似物、10种结构不同的H-1配体和其他几种cns活性化合物的比较显示，[H-3]-(-)-反式h -2-PAT位点与[H-3]新锥体标记的H-1受体的亲和力没有显著差异。这些结果，加上先前的自放射成像脑受体定位研究表明[H-3]-(-)-反式- h -2- pat位点和[H-3]新锥体标记的H-1受体分布相似，表明这两种放射性配体在啮齿动物大脑中标记相同的组胺H-1受体。我们还报告了对我们之前对PAT配体的比较分子场分析（CoMFA）研究的修订，该研究产生了66种化合物的高度预测模型，交叉验证的R-2 （q(2)）值为0.67。该模型可用于预测哺乳动物脑内放射性标记H-1受体的高亲和力配体。
A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to modulate tyrosine hydroxylase activity and dopamine synthesis in rodent forebrain through interaction with a binding site labeled by [H-3]-(-)-(1R, 3S)-trans-H-2-PAT. Recently, we have discovered that PATs also bind with high affinity to the [H-3]-mepyramine-labeled H-1 receptor in rat and guinea pig brain. Here, we report the synthesis and biological evaluation of additional PAT analogues in order to identify differences in binding at these two sites. Further molecular modifications involve the pendant phenyl ring as well as quaternary amine compounds. Comparison of about 38 PAT analogues, 10 structurally diverse H-1 ligands, and several other CNS-active compounds revealed no significant differences in affinity at [H-3]-(-)-trans-H-2-PAT sites versus [H-3]mepyramine-labeled H-1 receptors. These results, together with previous autoradiographic brain receptor-mapping studies that indicate similar distribution of [H-3]-(-)-trans-H-2-PAT sites and [H-3]mepyramine-labeled H-1 receptors, suggest that both radioligands label the same histamine H-1 receptors in rodent brain. We also report a revision of our previous comparative molecular field analysis (CoMFA) study of the PAT ligands that yields a highly predictive model for 66 compounds with a cross-validated R-2 (q(2)) value of 0.67. This model will be useful for the prediction of high-affinity ligands at radiolabeled H-1 receptors in mammalian brain.