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Published on: July 29, 2014
Peripherally restricted opioid agonists as novel analgesic agents
D L DeHaven-Hudkins1, R E Dolle
1Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA. ddehavenhudkins@adolor.com
Current Pharmaceutical Design
|March 23, 2004
Summary
Targeting peripheral opioid receptors offers pain relief without central nervous system side effects. This review explores methods and compounds for achieving peripheral opioid analgesia, focusing on inflammatory and visceral pain.
Area of Science:
- Pharmacology
- Neuroscience
- Medicinal Chemistry
Background:
- Peripheral opioid receptors mediate antinociception, offering a strategy for analgesia with reduced central nervous system side effects.
- These receptors are crucial in inflammatory pain, pruritus, and visceral pain transmission.
- Developing peripherally acting opioids requires overcoming challenges related to drug distribution and receptor selectivity.
Purpose of the Study:
- To review medicinal chemistry strategies for peripheralizing opioid agonists.
- To discuss in vivo assays used for identifying peripherally selective compounds.
- To evaluate compounds with demonstrated in vivo peripheralization.
Main Methods:
- Medicinal chemistry modifications (lipophilicity, hydrophilicity, amphiphilicity) of central opioid agonists.
- Chemical strategies like quaternization and use of mdr transporter substrates to limit brain penetration.
- In vivo behavioral and pharmacokinetic assays to assess peripheral selectivity.
Main Results:
- Various chemical modifications can influence opioid distribution and target peripheral receptors.
- In vivo assays provide data on compound efficacy and pharmacokinetic profiles.
- Several compounds show promise for peripheral opioid analgesia, though predictability varies.
Conclusions:
- Peripheral opioid receptor targeting is a promising avenue for effective pain management.
- Medicinal chemistry and robust in vivo testing are key to developing peripherally selective analgesics.
- Further research is needed to optimize compounds and assays for clinical translation.
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