Thomas J B, Zheng X, Mascarella S W, Rothman R B, Dersch C M, Partilla J S, Flippen-Anderson J L, George C F, 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 Oct 8;41(21):4143-9. doi: 10.1021/jm980290i.
The inhibition of radioligand binding and [35S]GTPgammaS functional assay data for N-methyl- and N-phenethyl-9beta-methyl-5-(3-hydroxyphenyl)morphans (5b and 5c) show that these compounds are pure antagonists at the micro, delta, and kappa opioid receptors. Since 5b and 5c have the 5-(3-hydroxyphenyl) group locked in a conformation comparable to an equatorial group of a piperidine chair conformation, this information provides very strong evidence that opioid antagonists can interact with opioid receptors in this conformation. In addition, it suggests that the trans-3, 4-dimethyl-4-(3-hydroxyphenyl)piperidine class of antagonist operates via a phenyl equatorial piperidine chair conformation. Importantly, the close relationship between the 4-(3-hydroxyphenyl)piperidines and 5-(3-hydroxyphenyl)morphan antagonists shows that the latter class of compound provides a rigid platform on which to build a novel series of opioid antagonists.
N-甲基和N-苯乙基-9β-甲基-5-(3-羟基苯基)吗啡烷（5b和5c）的放射性配体结合抑制及[35S]GTPγS功能测定数据表明，这些化合物在μ、δ和κ阿片受体上是纯拮抗剂。由于5b和5c的5-(3-羟基苯基)基团锁定在与哌啶椅式构象的赤道基团相当的构象中，该信息提供了非常有力的证据，证明阿片拮抗剂可以以这种构象与阿片受体相互作用。此外，这表明反式-3,4-二甲基-4-(3-羟基苯基)哌啶类拮抗剂通过苯基赤道哌啶椅式构象起作用。重要的是，4-(3-羟基苯基)哌啶与5-(3-羟基苯基)吗啡烷拮抗剂之间的密切关系表明，后一类化合物提供了一个刚性平台，可在此基础上构建一系列新型阿片拮抗剂。
