posted on 2006-12-14, 00:00authored byBertrand Le Bourdonnec, Allan J. Goodman, Mathieu Michaut, Hai-Fen Ye, Thomas M. Graczyk, Serge Belanger, Torsten Herbertz, Glenn P. A. Yap, Robert N. DeHaven, Roland E. Dolle
The series of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have been widely investigated as opioid
receptor antagonists. One of our research goals was to explore the bioactive conformation of the N-phenethyl
trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine derivative 3, prototypical μ-opioid antagonist in this series.
In this effort, the rotational degrees of freedom of the N-substituent of 3 were limited by incorporation of
an ethylene bridge between the piperidine 2- or 6-position of 3 and the benzylic position of the N-phenethyl
moiety. The overall modification led to a novel series of fused bicyclic derivatives of the octahydroquinolizine
chemical class, conformationally restricted analogue of 3. The constrained analogues 6 and 9 showed high
affinity toward the μ-opioid receptor. Compound 6 was found to be a μ-opioid antagonist, whereas the
constrained analogue 9 displayed potent μ-agonist activity in vitro. This study provides additional information
about the molecular determinants for μ recognition, the structural features affecting ligand binding, and the
structure function relationships.