Background: The main aim of synthesizing permanently charged opioids is to
ensure that they do not enter the central nervous system. Such drugs can provide analgesic
activity with reduced sedation and other side effects on the central nervous system.
Methods: We undertook a search of bibliographic databases for peer-reviewed research
literature and also summarized our published results in this field.
Results: The present review focuses on the characterization of permanently charged
opioids by various physicochemical methods, and in vitro as well as in vivo tests. The basicity
and lipophilicity of opioid alkaloids are discussed at the microscopic, speciesspecific
level. Glucuronide conjugates of opioids are also reviewed. Whereas the primary
metabolite morphine-3-glucuronide does not bind to opioid receptors with high affinity,
morphine-6-glucuronide is a potent analgesic, at least, partly due to its unexpectedly high
lipophilicity. We discuss the quaternary ammonium opioid derivatives of a permanent
positive charge, detailing their antinociceptive activity and effects on gastrointestinal motility
in various in vivo animal tests and in vitro studies. Compounds with antagonistic activity
are also reviewed. The last part of our study concentrates on sulfate conjugates of
morphine derivatives that display unique pharmacological properties because they carry a
negative charge at any pH value in the human body.
Conclusion: In conclusion, the findings of this review confirm the importance of permanently
charged opioids in the investigated fields of pharmacology.