Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methyl

详细信息    查看全文

• 作者：Chad M. Kormos ; Moses G. Gichinga ; Rangan Maitra ; Scott P. Runyon ; James B. Thomas ; Lawrence E. Brieaddy ; S. Wayne Mascarella ; Hern谩n A. Navarro ; F. Ivy Carroll
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7367-7381
• 全文大小：553K
• ISSN：1520-4804

文摘

JDTic analogues 4鈥?b>15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the 渭, 未, and 魏 opioid receptors determined and compared to JDTic using [p>35p>S]GTP纬S assays. Compounds 4, 5, 6, 13, 14, and 15 had K_e = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the K_e = 0.02 nM for JDTic at the 魏 receptor and were highly selective for the 魏 receptor relative to the 渭 and 未 opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective 魏 opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.