? Morphine is the drug of choice for the management of severe pain due to its central actions at mu opioid receptors. With repeated administration, patients become tolerant to the analgesic effects. Tolerance to peripheral opioid receptors develops more slowly, resulting in differential tolerance and an exacerbated constipatory effect. It is hypothesized that efflux transporters at the Blood-Brain Barrier play a role in the development of differential tolerance. P-glycoprotein (P-gp) is up regulated in morphine tolerant animals and morphine is a P-gp substrate. Therefore, the design of opioids with decreased activity as P-gp substrates will result in analgesics with reduced constipation. The removal of 3-phenol groups in 4,5-epoxymorphinans is hypothesized to decrease P-gp affinity and is known to reduce potency at opioid receptors. The highly potent mu agonist etorphine has similar P-gp substrate affinity to morphine. Replacement of the 3-phenol of etorphine will therefore reduce P-gp substrate activity and bring opioid potency to a therapeutic level in humans. Replacements at the 20-position will refine potency of the resulting weak P-gp substrates. The long-term goal is to develop novel therapeutics for the treatment of chronic, severe pain. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA021049-02
Application #
7284109
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$26,522
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Healy, Jason R; Bezawada, Padmavani; Griggs, Nicholas W et al. (2017) Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands. Bioorg Med Chem Lett 27:666-669
Metcalf, Matthew D; Rosicky, Andrew D; Hassan, Hazem E et al. (2014) Opioids and efflux transporters. Part 4: influence of N-substitution on P-glycoprotein substrate activity of noroxymorphone analogues. Bioorg Med Chem Lett 24:3592-5
Cunningham, Christopher W; Mercer, Susan L; Hassan, Hazem E et al. (2008) Opioids and efflux transporters. Part 2: P-glycoprotein substrate activity of 3- and 6-substituted morphine analogs. J Med Chem 51:2316-20