Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3-and 4-methyl substituents
Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3-and 4-methyl substituents
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DOI：
10.1016/j.bmc.2015.08.025
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发表时间：
2015-10-01
影响因子：
3.5
通讯作者：
Navarro, Hernan A.
中科院分区：
文献类型：
--
作者：
Carroll, F. Ivy;Gichinga, Moses G.;Navarro, Hernan A.
JDTic作为一种有效的和选择性的κ阿片受体拮抗剂的设计和发现使用N-取代的反式-3，4-二甲基-4-（3-羟基苯基）哌啶药效团作为先导结构。为了确定JDTic和JDTic类似物中3-甲基或4-甲基是否是拮抗活性所必需的，合成了分别从JDTic和类似物中除去3-甲基或3-和4-甲基的化合物4a-c和4d-f，并使用[S-35] GTP γ S结合测定法评价其体外阿片受体拮抗剂活性。还评估了所选化合物的其他ADME性质。这些研究表明，JDTic和类似物中存在的3-甲基或3，4-二甲基基团都不是产生有效和选择性κ阿片受体拮抗剂所必需的。(C)2015爱思唯尔有限公司版权所有。
The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [S-35] GTP gamma S binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective kappa opioid receptor antagonists. (C) 2015 Elsevier Ltd. All rights reserved.