Cueva Juan Pablo, Cai Tingwei Bill, Mascarella S Wayne, Thomas James B, Navarro Hernán A, Carroll F Ivy
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Post Office Box 12194, Research Triangle Park, North Carolina 27709-2194, USA.
J Med Chem. 2009 Dec 10;52(23):7463-72. doi: 10.1021/jm900756t.
In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [(35)S]GTPgammaS binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K(e) values at the kappa receptor. The three most potent analogues were the monomethylated (3R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8e) with K(e) values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K(e) = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the micro and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.
在先前的构效关系（SAR）研究中，（3R）-7-羟基-N-[(1S)-1-{[(3R,4R)-4-(3-羟基苯基)-3,4-二甲基-1-哌啶基]甲基}-2-甲基丙基]-1,2,3,4-四氢-3-异喹啉甲酰胺（JDTic，3）被确定为首个从反式-3,4-二甲基-4-(3-羟基苯基)哌啶类阿片受体拮抗剂中筛选出的强效且选择性κ-阿片受体拮抗剂。在本研究中，我们报告了3的类似物8a - p的合成，并使用[(35)S]GTPγS结合试验展示了它们的体外阿片受体功能拮抗作用。化合物8a - p是3的类似物，在五个不同位置连接有一个、两个或三个与JDTic结构相连的甲基。除8k外，所有添加了一个和两个甲基的类似物在κ受体处的K(e)值均低于纳摩尔。三种最有效的类似物分别是单甲基化的（3R）-7-羟基-N-[(1S,2S)-1-{[(3R,4R)-4-(3-羟基苯基)-3,4-二甲基哌啶-1-基]甲基}-2-甲基丁基]-1,2,3,4-四氢异喹啉-3-甲酰胺（8a）和（3R）-7-羟基-N-[(1S)-1-{[(3R,4R)-4-(3-羟基苯基)-3,4-二甲基哌啶-1-基]甲基}-(2-甲基丙基)]-3-甲基-1,2,3,4-四氢异喹啉-3-甲酰胺（8e），它们在κ受体处的K(e)值为0.03 nM，以及（3R）-7-羟基-N-[(1S)-1-{[(3R,4R)-4-(3-甲氧基苯基)-3,4-二甲基哌啶-1-基]甲基}-2-甲基丙基]-1,2,3,4-四氢异喹啉-3-甲酰胺（8d），其在κ受体处的K(e) = 0.037 nM。相对于μ和δ受体，这三种化合物对κ受体均具有选择性。总体而言，本研究结果突出了3上耐受取代的区域。
