Synthesis and physicochemical characterization of new potential haptens and their precursors with morphine skeleton

Abstract

Opiate analgetics are widely used therapeutic agents, but their side-effects can cause serious harm to users, and they are often abused for their euphoric effects. Their abuse is a serious healthcare problem worldwide, and in addition, pharmacological treatments of this disorder possess serious problems such as adverse effects, medication adherence complications, and relapse to addiction after the therapy. One possible way to combat the latter issue would be vaccination with macromolecule-opiate conjugates. Therefore, novel compounds are necessary not just as potential therapeutic agents, but also as new hapten-like molecules. In this work, we present the synthesis of novel N-cyanoalkyl- and N-aminoalkyl-noropiate derivatives, which could be used either as new therapeutic agents or haptens.

An important aim of this work was to quantify biorelevant physicochemical properties (basicity, lipophilicity) of the newly synthesized compounds. The determination of the protonation macroconstants characterizing the acid-base properties was performed by pH-potentiometry. To determine the partition coefficients, we used the shake-flask method with different octanol/water phase ratios. The complex formation of the pharmacologically active N-cyanoalkyl derivatives with β-cyclodextrin was also investigated. The stoichiometry of the β-cyclodextrin complexes was determined by the Job's plot method, their structure by NMR spectroscopy, and their stability by NMR and circular dichroism spectroscopy. The study of this complex opens up the possibility of a more in-depth formulation investigation. The species-specific basicity of the new potential aminoalkyl haptens was also characterized, which can help further structure-activity relationship studies.