Morphine (1) and codeine (2) are two representatives of medically important, frequently used natural opiates, therefore the exploration of their metabolic pathways and the exact characterization of the metabolites are main targets of their pharmacological studies. These morphinans also play a crucial role in drug abuse; therefore, the analysis and preparation of the metabolites for identification and quantitation in human samples are considered important aims. In order to allow the in-depth analysis of metabolites derived from the oxidative pathways through morphinone (3) and codeinone (4), synthetic procedures have been elaborated for the gram-scale preparation of glutathione and N-acetylcysteine adducts. Primary pharmacological studies revealed the inactive nature of these metabolites in opioid receptor binding tests.
Novel 6-ketolevorphanol analogs with diverse substitution patterns at ring C were synthesized and their binding affinities at the μ,δ and κ opioid receptors were investigated. The in vitro activity of the new analogs was then evaluated in the functional assay based on the electrically-stimulated contractions of the mouse ileum. It was shown that analogs with Δ7,8 bond had no significant potency at any of the opioid receptor types. In contrast, analogs with the saturated ring C were either potent κ agonist or antagonist depending on the absence or presence of the hydroxyl group in position 14.
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