Design, Synthesis, and Biological Evaluation of Structurally Rigid Analogues of 4‑(3-Hydroxy­phenyl)­piperidine Opioid Receptor Antagonists

In order to gain additional information
concerning the active conformation
of the N-substituted trans-3,4-dimethyl-4-(3-hydroxy­phenyl)­piperidine
(1) class of opioid receptor antagonists, procedures
were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxy­phenyl)­3-azabicyclo­[3.1.0]­hexane
and 3-methyl-4-(3-hydroxy­phenyl)-4-azabicyclo­[4.1.0]­heptanes.
Evaluation of the conformationally constrained series in a [35S]­GTPγS assay showed that structural rigid compounds having
the 3-hydroxyphenyl group locked in the piperidine equatorial orientation
had potencies equal to or better than similar compounds having more
flexible structures similar to 1. The studies of the
rigid compounds also suggested that the 3-methyl group present in
compound 1 type antagonists may not be necessary for
their pure opioid antagonist properties.