Opiate alkaloids and their synthetic derivatives are still widely used in pain management,
drug addiction, and abuse. To avoid serious side effects, compounds with properly
designed pharmacological profiles at the opioid receptor subtypes are long needed.
Here a series of 17- N -substituted derivatives of normorphine and noroxymorphone
analogues with five- and six-membered ring substituents have been synthesized for
structure–activity study. Some compounds showed nanomolar affinity to MOR, DOR and
KOR in in vitro competition binding experiments with selective agonists [ 3 H]DAMGO,
[ 3 H]Ile 5,6 -deltorphin II and [ 3 H]HS665, respectively. Pharmacological characterization
of the compounds in G-protein signaling was determined by [ 35 S]GTPγS binding assays.
The normorphine analogues showed higher affinity to KOR compared to MOR and DOR, while
most of the noroxymorphone derivatives did not bind to KOR. The presence of 14-OH
substituent resulted in a shift in the pharmacological profiles in the agonist > partial
agonist > antagonist direction compared to the parent compounds. A molecular docking-based
in silico method was also applied to estimate the pharmacological profile of the compounds.
Docking energies and the patterns of the interacting receptor atoms, obtained with
experimentally determined active and inactive states of MOR, were used to explain
the observed pharmacological features of the compounds.
