• Pan, Ying-Xian (PI)
  • Pasternak, Gavril W. (PI)

Project Details


Na1BzoH (6-desoxy-6-benzoylhydrazido-N-allyl-14-
hydroxydihydronormorphinone) is a novel opiate active at both mu and kappa
receptors. In the presence of Mg++ ions, 3H-NalBzoH labels mu receptors
pseudoirreversibly, with a remarkably prolonged rate of dissociation which
is 145-fold slower than 3H-naloxone. The binding is not covalent since the
GTP analog Gpp(NH)p rapidly dissociates the ligand, presumably by
interrupting a stabilized receptor-G-protein complex. 3H-NalBzoH also
labels a novel kappa receptor subtype present in high densities in calf,
rat and mouse brains, kappa3. In vivo, NalBzoH is a potent, long-acting mu
antagonist, blocking morphine analgesia for over 24 hr after a single dose.
Low doses of NalBzoH also partially reverse the inhibition of GI transit
produced by morphine, completely antagonize morphine lethality and
precipitate withdrawal in morphine-dependent mice. Higher NalBzoH doses
produce analgesia through a kappa receptor mechanism based upon its
sensitivity towards a series of antagonists. NalBzoH has excellent oral
activity, with a potency equivalent to the subcutaneous route. Thus,
NalBzoH has several potential advantages over traditional opiates and could
be useful as either a long-acting antagonist or a nonabusable analgesic.
We propose to examine the features which distinguish NalBzoH from
traditional opiates: 1) its prolonged duration of mu receptor antagonism,
2) its potent kappa analgesia and 3) its excellent oral potency. We will
determine whether the prolonged mu receptor antagonism results from
pharmacokinetic factors, such as a slow clearance, or whether it
corresponds to its ability to label mu receptors pseudoirreversibily. We
will determine half-lives of distribution and elimination, volumes of
distribution and clearances. Efforts will be made to identify active major
metabolites. Using 3H-NalBzoH, we also will investigate the formation of
psuedoirreversible mu binding following NalBzoH administration in vivo. We
will synthesize a series of analogs of NalBzoH to be examined in binding
studies looking at their ability to label mu receptors pseudoirreversibly
and their affinity at a variety of opiate receptor subtypes, especially
kappa3. Selected derivatives will be synthesized in radiolabeled form and
their binding directly examined. Additional derivatives will be examined
in vivo. Finally, we will compare the metabolism and pharmacokinetics of
NalBzoH following both oral and intravenous administration.
Effective start/end date7/1/906/30/19


  • National Institute on Drug Abuse: $464,335.00


  • Psychiatry and Mental health
  • Medicine(all)
  • Neuroscience(all)
  • Pharmacology


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