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Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest.

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.

SUBMITTER: Mazak K

PROVIDER: S-EPMC6610444 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest.

Mazák Károly K Noszál Béla B Hosztafi Sándor S

ChemistryOpen 20190704 7

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 propert ...[more]

PMID: 31312587

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Project description:Opioids are widely used for treating different types of pains, but overuse and abuse of prescription opioids have led to opioid epidemic in the United States. Besides analgesic effects, chronic use of opioid can also cause tolerance, dependence, and even addiction. Effective treatment of opioid addiction remains a big challenge today. Studies on addictive effects of opioids focus on striatum, a main component in the brain responsible for drug dependence and addiction. Some transcription regulators have been associated with opioid addiction, but relationship between analgesic effects of opioids and dependence behaviors mediated by them at the molecular level has not been thoroughly investigated. In this paper, we developed a new computational strategy that identifies novel targets and potential therapeutic molecular compounds for opioid dependence and addiction. We employed several statistical and machine learning techniques and identified differentially expressed genes over time which were associated with dependence-related behaviors after exposure to either morphine or heroin, as well as potential transcription regulators that regulate these genes, using time course gene expression data from mouse striatum. Moreover, our findings revealed that some of these dependence-associated genes and transcription regulators are known to play key roles in opioid-mediated analgesia and tolerance, suggesting that an intricate relationship between opioid-induce pain-related pathways and dependence may develop at an early stage during opioid exposure. Finally, we determined small compounds that can potentially target the dependence-associated genes and transcription regulators. These compounds may facilitate development of effective therapy for opioid dependence and addiction. We also built a database (http://daportals.org) for all opioid-induced dependence-associated genes and transcription regulators that we discovered, as well as the small compounds that target those genes and transcription regulators.

Project description:Background: This study sought to explore whether intervening in suspected cases of opioid overdose alters interest in treatment for opioid use disorder (OUD). Data were collected as a part of a trial comparing the effects of different overdose education and naloxone distribution (OEND) training curricula on overdose outcomes. Methods: Following OEND training, participants completed four in-person follow-up visits at 1-, 3-, 6- and 12-months. Participants were also regularly contacted to inquire about overdose events they responded to, witnessed, or experienced themselves. Other assessments included the Addiction Severity Index that queries participants' perceived importance of drug treatment on a scale of: 0 (Not at All) to 4 (Extremely). For the current secondary data analysis, treatment importance was assessed at the time points most immediately preceding and following participant intervention in an overdose event using naloxone. Results: The sample reported a mean duration of opioid use of 14.9 (± 11.5) years, with 67% having witnessed an overdose event prior to the study. Of the 321 enrolled, 92 participants used naloxone in response to 166 suspected cases of an opioid overdose. For the entire sample, mean treatment importance did not significantly change throughout the study. Among participants who utilized naloxone, treatment importance increased following the event (Before: 3.03, After: 3.39, p = 0.02). Due to the amount of time between the overdose event and assessment of post-event treatment importance (40.5 days, ±40.2), the current study most likely underestimates this effect. Conclusions: The current study suggests that responding to an overdose event increases interest in OUD treatment. Currently only considered an acute intervention to reduce overdose morbidity and mortality, OEND may have the potential to increase enrollment in medications to treat OUD. However, a prospective investigation needs to determine if the impact of an overdose event could be utilized to increase treatment engagement.

Dataset Information

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest.

Publications

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest.

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