Morphine and its derivatives play inevitably important role in the m-opioid receptor
(MOR) targeted antinociception. A structure-activity relationship study is presented
for novel and known orvinol and thevinol derivatives with varying 3-O, 6-O, 17-N and
20-alkyl substitutions starting from agonists, antagonists and partial agonists. In
vitro competition binding experiments with [3H]DAMGO showed low subnanomolar affinity
to MOR. Generally, 6-O-demethylation increased the affinity toward MOR and decreased
the efficacy changing the pharmacological profile in some cases. In vivo tests in
osteoarthritis inflammation model showed significant antiallodynic effects of thevinol
derivatives while orvinol derivatives did not. The pharmacological character was modelled
by computational docking to both active and inactive state models of MOR. Docking
energy difference for the two states separates agonists and antagonists well while
partial agonists overlapped with them. An interaction pattern of the ligands, involving
the interacting receptor atoms, showed more efficient separation of the pharmacologicalprofiles.
In rats, thevinol derivatives showed antiallodynic effect in vivo. The orvinol derivatives,
except for 6-O-desmethyl-dihydroetorfin (2c), did not show antiallodynic effect
