Thomas J B, Mascarella S W, Rothman R B, Partilla J S, Xu H, McCullough K B, Dersch C M, Cantrell B E, Zimmerman D M, Carroll F I
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 1998 May 21;41(11):1980-90. doi: 10.1021/jm980063g.
A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor.
使用一组刚性与柔性N-取代基，对(+)-(3R,4R)-二甲基-4-(3-羟基苯基)哌啶(4)衍生物的N-取代基相关结合位点要求进行了研究。研究表明，带有反式肉桂基N-取代基的化合物7-9最接近先前报道的柔性N-丙基苯基或N-丙基环己基类似物在阿片受体上的效力。N-取代的顺式肉桂基化合物和顺式苯基环丙基甲基化合物10和11分别对阿片受体均未表现出高亲和力。然而，N-反式苯基环丙基甲基化合物12的亲和力与化合物7-9相近。此外，我们发现苯环的自由旋转对于高亲和力结合和μ受体亚型选择性是必要的，因为平面N-取代的噻萘基甲基和苯并呋喃基甲基化合物13和14的结合亲和力显著较低。总之，这些发现表明，(+)-(3R,4R)-二甲基-4-(3-羟基苯基)哌啶(4)的N-丙基苯基或N-丙基环己基类似物的高结合亲和力、选择性和拮抗剂效力是通过一种构象实现的，其中N-取代基的连接链从哌啶氮延伸开，且附加的环系统相对于连接链原子旋转出平面。如通过单晶X射线分析所确定的，这种构象与在固态下观察到的5的构象非常相似。此外，还发现，与纳曲酮不同，带有直接连接到4的哌啶氮上的仲碳的N-取代基与未以这种方式取代的类似物相比，效力会大幅降低。使用测量[35S]GTP-γ-S结合的刺激或抑制的功能测定法，我们表明(+)-(3R,4R)-二甲基-4-(3-羟基苯基)哌啶(4)的反式肉桂基类似物保留了阿片纯拮抗剂活性，并在μ受体上具有皮摩尔级的拮抗剂效力。
