Probes for narcotic receptor mediated phenomena.: 34.: Synthesis and structure-activity relationships of a potent μ-agonist δ-antagonist and an exceedingly potent Antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series
Probes for narcotic receptor mediated phenomena.: 34.: Synthesis and structure-activity relationships of a potent μ-agonist δ-antagonist and an exceedingly potent Antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series
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DOI：
10.1021/jm061325e
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发表时间：
2007-08-09
影响因子：
7.3
通讯作者：
Rice, Kenner C.
中科院分区：
文献类型：
--
作者：
Hiebel, Anne-Cecile;Lee, Yong Sok;Rice, Kenner C.
合成了具有C9-甲基、C9-亚甲基、C9-酮、C9-羟基取代基和C9-羟基取代基的5-（3-羟基苯基）- n -苯乙基morphan对映体，并对其进行了药理学评价。10个化合物中的3个，(1R,5R,9S)-(-)-9-羟基-5-(3-羟基苯基-2-苯乙基-2-氮扎比环[3.3.1]壬烷((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-（3-羟基苯基）-9-亚甲基-2-苯乙基-2-氮扎比环[3.3]。我]壬烷((IR、5 s) -(+) -14),和(IR, 5 s, 9 r) - (-) 5 - (3-hydroxyphenyl) 9-methyl-2-phenethyl-2-azabicyclo -[3.3。壬烷(（lR,5S,9R)-(+)-15）对μ -阿片受体具有亚纳摩尔亲和力（K-i分别为0.19,0.19和0.63 nM）。在[35S] gtp - γ - s试验中，(1R,5S)-(+)-14被发现是一种阿片受体激动剂和mu-、delta-和kappa-拮抗剂，在许多急性和亚慢性疼痛试验中，包括伤害感觉的热模型和内脏模型，其效力约为吗啡的50倍。具有C9-羟基取代基的(I R,5R,9S)-(-)-10化合物轴向指向哌啶环（C9 -羟基）是一种比吗啡强约500倍的受体激动剂。在单剂量抑制实验中，其效力大于吗啡的1000倍。它是已知最有效的苯吗啡类抗痛觉药。利用密度泛函理论在B3LYP/6-31G*能级上对这些化合物的分子结构进行能量最小化，然后利用morphan片段中的重原子作为公共对接点覆盖在(IR,5R,9S)-(-)-10上。基于模型，(lR,5R,9S)-(-)-10中质子化氮原子和9 - β - oh取代基的空间排列可能有助于假设的水链的排列，从而使质子转移到μ -阿片受体中附近的质子受体基团。
Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9 alpha-methyl, C9-methylene, C9-keto, and C9 alpha- and C9 beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3. I]nonane ((IR,5S)-(+)-14), and (IR,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo-[3.3. I]nonane ((lR,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (K-i = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (I R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9 beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (IR,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9 beta-OH substituent in (lR,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the,mu-opioid receptor.