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Review
. 2019 Jul 4;8(7):879-887.
doi: 10.1002/open.201900115. eCollection 2019 Jul.

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

Károly Mazák  1 , Béla Noszál  1 , Sándor Hosztafi  1
Affiliations
Review

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

Károly Mazák et al. ChemistryOpen. .

Abstract

This review focuses on recent developments in the physicochemical profiling of morphine and other opioids. The acid-base properties and lipophilicity of these compounds is discussed at the microscopic, species-specific level. Examples are provided where this type of information can reveal the mechanism of pharmacokinetic processes at the submolecular level. The role of lipophilicity in quantitative structure-activity relationship (QSAR) studies of opioids is reviewed. The physicochemical properties and pharmacology of the main metabolites of morphine are also discussed. Recent studies indicate that the active metabolite morphine-6-glucuronide (M6G) can contribute to the analgesic activity of systemically administered morphine. The unexpectedly high lipophilicity of M6G partly accounts for its analgesic activity. When administered parenterally, another suspected minor metabolite, morphine-6-sulfate (M6S) has superior antinociceptive effects to those of morphine. However, because sulfate esters of morphine derivatives cannot cross the blood-brain barrier these esters may be good candidates to develop peripheral analgesic drugs.

Keywords: basicity; glucuronide conjugates; lipophilicity; opioids; physicochemical profiling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The protonation scheme and equilibria of naloxone in terms of macroscopic (K 1, K 2) and microscopic (k N, k°,kON ,kNO ) protonation constants.
Figure 2
Figure 2
The structure of some important semisynthetic opioid compounds.
Figure 3
Figure 3
Distribution of naloxone microspecies, as a function of pH.
Figure 4
Figure 4
The lipophilicity profile of naloxone (broad black line), and the contribution of its four microspecies (thin lines) to the overall lipophilicity.
Figure 5
Figure 5
The protonation scheme of M6G.
Figure 6
Figure 6
The distribution diagram of M6G macrospecies, as a function of pH.
Figure 7
Figure 7
Contribution of the four macrospecies of M6G to the lipophilicity profile (broad black line).
See this image and copyright information in PMC

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