Thesis-1994-Martin.pdf (3.44 MB)
Biochemical and pharmacological studies of morphine-6-glucuronide and related compounds
thesis
posted on 2014-01-03, 11:23 authored by Jason Lewis MartinMorphine-6-glucuronide is a minor metabolite. representing 5% of an
administered dose of morphine. The metabolite has analgesic activity
exceeding that of morphine and may contribute to analgesia following
morphine administration.
The aims of the study were to attempt to identify the reasons behind the
improved activity of morphine-6-glucuronide over the parent compound
and to examine a series of 6-substituted compounds, based on 6-substituted
benzoate esters, as potential mimics of morphine-6-glucuronide.
Morphine-6-glucuronide was seen to have similar affinity to morphine at
l1-opioid receptors as assessed by ligand-binding assays in mouse brain
homogenates. However a three-fold improved affinity at S-opioid receptor
binding sites was observed and a ten-fold reduction in affinity at K-opioid
sites. Using in vitro bioassay systems the glucuronide showed a two-fold
improved potency over morphine in both the guinea-pig ileum and the
mouse vas deferens preparations. Following in vivo (s.c.) administration in
the mouse the glucuronide was seen to be equipotent with morphine in the
tail-flick test, but was of much longer duration, lasting up to 9 hours. Exvivo
binding assays confirmed that morphine-like material was still
present in the central nervous system six hours after administration of the
glucuronide, but was not observed at a similar time after morphine
administration. Activity was retained if the hydroxyl groups of the sugar
moiety of the glucuronide were protected as esters. In contrast the more
prevalent morphine metabolite morphine-3-glucuronide was inactive in
all in vitro and in vivo tests used and did not antagonise morphine in
vitro or in vivo. A group of 3-substituted derivatives containing saturated
and unsaturated substituents did show affinity for opioid receptors but no
agonist activity of the compounds could be demonstrated in vitro. A series of synthetic 6-substituted compounds showed a variety of affinities
for, and agonist potencies at, opioid receptors, though low affinity at Kopioid
receptors was a general finding. For example, morphine-6-
nitrobenzoate was l1-opioid receptor preferring, while morphine-6-
phthalate had improved O-opioid receptor affinity and acted via Il-opioid
receptors in the mouse vas deferens and in vivo. However the compounds
were weaker than morphine and the duration of action in vivo was shorter
than morphine-6-glucuronide.
The conclusions from these studies are that morphine-6-glucuronide and
morphine have similar in vitro affinities at the l1-receptor, although
morphine-6-glucuronide has somewhat improved binding affinity for Il
receptor sites, it has less affinity for K receptor sites. Pharmacokinetic
reasons are probably responsible for the improved activity and duration of
action of morphine-6-glucuronide over morphine. None of the synthetic
compounds examined are potentially useful as direct mimics of the
glucuronide because morphine-6-glucuronide is more potent and has a
longer duration of action than the synthetic derivatives, though alteration
at the 6-position of the morphine nucleus can lead to dramatic changes in
selectivity and potency of ligands for the differing opioid receptors.
History
School
- Science
Department
- Chemistry
Publisher
© Jason Lewis MartinPublication date
1994Notes
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.Language
- en