Weltrowska Grazyna, Lemieux Carole, Chung Nga N, Guo Jason J, Wilkes Brian C, Schiller Peter W
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, QC H2W 1R7, Canada.
Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA.
Bioorg Med Chem. 2014 Sep 1;22(17):4581-6. doi: 10.1016/j.bmc.2014.07.033. Epub 2014 Jul 29.
There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we synthesized 'carba'-analogues of the highly potent μ opioid analgesic carfentanil (3), in which the piperidine nitrogen was replaced with a carbon. The resulting trans isomer (8b) showed reduced, but still significant MOR binding affinity (Ki(μ)=95.2nM) with no MOR versus DOR binding selectivity and was a MOR partial agonist. The cis isomer (8a) was essentially inactive. A MOR docking study indicated that 8b bound to the same binding pocket as parent 3, but its binding mode was somewhat different. A re-evaluation of the uncharged morphine derivative N-formylnormorphine (9) indicated that it was a weak MOR antagonist showing no preference for MOR over KOR. Taken together, the results indicate that deletion of the positively charged nitrogen in μ opioid analgesics reduces MOR binding affinity by 2-3 orders of magnitude and may have pronounced effects on the intrinsic efficacy and on the opioid receptor selectivity profile.
有强有力的证据表明，内源性和外源性阿片样物质配体带正电荷的氮原子与阿片受体第三个跨膜螺旋中的天冬氨酸残基形成盐桥。为了进一步研究这种静电相互作用在阿片受体结合和激活中的作用，我们合成了强效μ阿片类镇痛药卡芬太尼（3）的“碳环”类似物，其中哌啶氮被碳取代。所得反式异构体（8b）显示出降低但仍显著的MOR结合亲和力（Ki(μ)=95.2nM），对MOR与DOR没有结合选择性，并且是MOR部分激动剂。顺式异构体（8a）基本无活性。一项MOR对接研究表明，8b与母体3结合在相同的结合口袋中，但其结合模式有所不同。对不带电荷的吗啡衍生物N-甲酰去甲吗啡（9）的重新评估表明，它是一种弱MOR拮抗剂，对MOR和KOR没有偏好。综上所述，结果表明，μ阿片类镇痛药中带正电荷氮原子的缺失使MOR结合亲和力降低2-3个数量级，并且可能对内在效力和阿片受体选择性谱产生显著影响。
