The main objective of this paper is to report the identification and synthesis of
norhydromorphone, a novel metabolite of
hydromorphone, and its antinociceptive activities when tested in the
formalin test as compared to other known
analgesics. In addition, we are reporting for the first time the lack of antinociceptive activities of
hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide in the rat
formalin test.
Norhydromorphone was isolated and identified as a metabolite of
hydromorphone in a
cancer patient's urine. An authentic standard of
norhydromorphone was synthesized. The identity of
norhydromorphone in the urine sample was confirmed by comparing the LC retention time and MS ion fragmentation with the synthetic standard using a liquid chromatographic-mass spectrometric-mass spectrometric (LC-MS-MS) assay.
Norhydromorphone was found to be a minor metabolite of
hydromorphone in the urine. Additionally, the antinociceptive activities of
norhydromorphone,
hydromorphone,
morphine,
dihydromorphine, dihydroisomorphine,
hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide were determined in the rat
formalin test following intraperitoneal (i.p.) administration. Only limited antinociception was observed and no significant increase in antinociception was detected at the three doses tested. The increased polarity of
norhydromorphone as compared to
hydromorphone due to the primary
piperidine nitrogen may make it less favorable to cross the blood-brain-barrier (BBB), which may be partly responsible. In addition, lower intrinsic antinociceptive activity, which remains to be determined, could also contribute to the low antinociception. Our results also show that
hydromorphone was five times as potent as
morphine in the
formalin test, while
dihydromorphine and dihydroisomorphine were equipotent to and 36% as potent as
morphine, respectively.
Hydromorphone-3-glucuronide, dihydromorphine-3-glucuronide and dihydroisomorphine-3-glucuronide did not exhibit any antinociceptive effect at the doses tested. The results further underscore the importance of a free C3-OH to the
analgesic effect of
morphine alkaloids.