Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents

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• 作者：F. Ivy Carroll ; ^{fic@rti.org" class="auth_mail" title="E-mail the corresponding author} ; Moses G. Gichinga ; Chad M. Kormos ; Rangan Maitra ; Scott P. Runyon ; James B. Thomas ; S. Wayne Mascarella ; Ann M. Decker ; Herná ; n A. Navarro
• 关键词：JDTic ; Opioids ; Kappa antagonist ; ADME properties
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：1 October 2015
• 年：2015
• 卷：23
• 期：19
• 页码：6379-6388
• 全文大小：867 K

文摘

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 [³⁵S]GTP纬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 魏 opioid receptor antagonists.