Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.

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Le Bourdonnec B, Goodman AJ, Michaut M, Ye HF, Graczyk TM, Belanger S, Herbertz T, Yap GP, DeHaven RN, Dolle RE

Elucidation of the bioactive conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of mu-opioid receptor antagonists.

J Med Chem. 2006 Dec 14;49(25):7278-89.

PubMed ID

17149858 [ View in PubMed

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Abstract

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 mu-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 mu-opioid receptor. Compound 6 was found to be a mu-opioid antagonist, whereas the constrained analogue 9 displayed potent mu-agonist activity in vitro. This study provides additional information about the molecular determinants for mu recognition, the structural features affecting ligand binding, and the structure function relationships.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Naloxone	Kappa-type opioid receptor	Ki (nM)	9.2	N/A	N/A	Details
Naloxone	Mu-type opioid receptor	IC 50 (nM)	7.3	N/A	N/A	Details
Naloxone	Mu-type opioid receptor	Ki (nM)	3.7	N/A	N/A	Details