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N-substituent modulation of opiate agonist/antagonist activity in resolved 3-methyl-3-(m-hydroxyphenyl)piperidines.

Abstract：

:A series of 3-methyl-3-(m-hydroxyphenyl)piperidines with N-substituent variations have been synthesized and resolved, and an X-ray crystal structure of one analogue was determined. The compounds have been characterized, pharmacologically, by detailed opiate receptor binding studies and determination of in vivo analgesia and opiate antagonism. The results indicate that all compounds bind with high selectivity and moderate affinity to mu-receptors with no qualitative difference between enantiomeric pairs. By contrast a striking difference in activities is found, with the (-) enantiomers being pure agonists and the (+) enantiomers having both agonist and antagonist activity. The effect of N-substituents on relative agonist and antagonist potency does not mimic that of fused ring opiates with the N-phenethyl compound, the most potent antagonist. These results together with the X-ray structure obtained suggest that agonist and antagonist activity is initiated by a bimodel binding of the compounds in two different orientations at the mu-receptor site.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Cheng A,Uyeno E,Polgar W,Toll L,Lawson JA,DeGraw JI,Loew G,Camerman A,Camerman N

doi

10.1021/jm00154a018

subject

Has Abstract

pub_date

1986-04-01 00:00:00

pages

531-7

issue

4

eissn

0022-2623

issn

1520-4804

journal_volume

29

pub_type

杂志文章

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