PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .12. CIS-(+)-3-METHYLFENTANYL ISOTHIOCYANATE, A POTENT SITE-DIRECTED ACYLATING AGENT FOR SIGMA-OPIOID RECEPTORS - SYNTHESIS, ABSOLUTE-CONFIGURATION, AND RECEPTOR ENANTIOSELECTIVITY
PROBES FOR NARCOTIC RECEPTOR MEDIATED PHENOMENA .12. CIS-(+)-3-METHYLFENTANYL ISOTHIOCYANATE, A POTENT SITE-DIRECTED ACYLATING AGENT FOR SIGMA-OPIOID RECEPTORS - SYNTHESIS, ABSOLUTE-CONFIGURATION, AND RECEPTOR ENANTIOSELECTIVITY
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DOI：
10.1021/jm00156a030
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发表时间：
1986-06-01
影响因子：
7.3
通讯作者：
KLEE, WA
中科院分区：
文献类型：
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作者：
BURKE, TR;JACOBSON, AE;KLEE, WA
通过对中间体3-甲基-N-苯基-4-哌啶(9)对映体的非对映异构体分析，合成了第一对不可逆阿片配体[(+)-和(-)-4]，光学纯度为99.6%。(-)-9的(R，R)-L-(+)-酒石酸盐的单晶X-射线分析表明其绝对构型为3S，4R。因此，由(-)-9衍生的(-)-3[顺式(-)-3-甲基芬太尼]和(-)-4的绝对构型为3S，4R，而(+)-3和(+)-4的绝对构型为3R，4S。研究表明，4(SuperFit)的(+)对映体对β-β的酰化反应具有很强的特异性。阿片受体(不包括.MU)在大鼠脑膜上，就像它的无手性原型一样(2)，在本实验中，其效力约为后者的10倍。在德尔塔的酰化反应中，(+)-4的效力约为FIT的5倍。NG108-15神经母细胞瘤中的受体胶质瘤杂交细胞，效力约为其对映体的50倍。FIT和(+)-4均表现为部分激动剂抑制ββ。在本实验中，NG108-15膜和(+)-4膜上的受体偶联腺苷环化酶的活性是FIT的5-10倍，是其对映体的100倍。胺12经二溴代、溴与氚气体催化交换、标记胺与硫代光气反应制得比活度为13cI/mmo1的[~3H]-(+)-4。以前的实验表明，(+)-4可以酰化同样的58000-道尔顿糖蛋白，以前证明是通过FIT酰化的，但非特异性标记较少。鉴于(+)-4的高效性和特异性及其对映体的可用性，这些化合物似乎可能被证明是研究阿片受体复合体的有价值的工具。
The first enantiomeric pair of irreversible opioid ligands [(+)- and (-)-4] were synthesized in > 99.6% optical purity as determined by HPLC analysis of diastereoisomeric derivatives of the intermediate 3-methyl-N-phenyl-4-piperidinamine (9) enantiomers. Single-crystal X-ray analysis of the (R,R)-L-(+)-tartaric acid salt of (-)-9 revealed the absolute configuration to be 3S,4R. The absolute configuration of (-)-3 [cis(-)-3-methylfentanyl] and (-)-4 derived from (-)-9 is thus 3S,4R and that of (+)-3 and (+)-4 is 3R,4S. The (+) enantiomer of 4 (SUPERFIT) was shown to be highly potent and specific for acylation of .delta. opioid receptors (to the exclusion of .mu.) in rat brain membranes like its achiral prototype FIT (2) and was about 10 times as potent as the latter in this assay. The (+)-4 was about 5 times as potent as FIT in acylation of .delta. receptors in NG108-15 neuroblastoma .times. glioma hybrid cells and about 50 times as potent as its enantiomer. Both FIT and (+)-4 behaved as partial agonists in inhibition of .delta. receptor coupled adenylate cyclase in NG108-15 membranes and (+)-4 was 5-10 times more potent than FIT and about 100 times more potent than its enantiomer in this assay. Dibromination of amine 12, catalytic exchange of bromine with tritium gas, and reaction of the labeled amine with thiophosgene afforded [3H]-(+)-4 with a specific activity of 13 Ci/mmol. Previous experiments indicated (+)-4 acylates the same 58000-dalton glycoprotein previously shown to be acylated by FIT but with less nonspecific labeling. In view of the high potency and specificity of (+)-4 and the availability of its enantiomer, it seems likely that these compounds will prove to be valuable tools for study of the opioid receptor complex.