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Introduction
(±)-Meptazinol (Figure1), with one chiral center in the structure,
is a potent analgesic similar to pethidine. Included in the British
Pharmacopoeia in 1998[1], (±)-meptazinol was recommended
by Hoskin and Hanks as one of six widely used agonist-antagonist
analgesics[2]. However, to date its analgesic mechanism
remains unknown. For example, we are still unsure if it is an agonist,
an antagonist, or even a mixed agonist-antagonist, and whether it
acts on one target or multiple targets.
During the early stages of development, meptazinol was regarded
as a mixed agonist-antagonist opioid analgesic based on the following
experimental evidence[3]: (i) the chemical structure
of meptazinol is similar to that of morphine (Figure 1); (ii) meptazinol-induced
analgesia is almost completely reversed by the opioid antagonist
naloxone, although higher doses are required to reverse meptazinol
compared to morphine; (iii) meptazinol is believed to be a selective
m opioid agonist[4]; and (iv) meptazinol reverses the
signs of acute morphine overdose in animals and precipitates abstinence
in animals rendered physically dependent on morphine.
However, unlike typical opiates whose notorious side-effects include
respiratory depression and addiction, meptazinol induces little
respiratory depression and has low addictive potential[5,6].
These properties make meptazinol quite similar to another analgesic,
tramadol[7] (Figure 1), which is believed to have multiple
analgesic mechanisms. Recent studies have also revealed that both
tramadol and meptazinol differ from opioid analgesics in the lack
of sensitization related to a low propensity to induce addition,
which might greatly reduce the possibility of their abuse[8].
Furthermore, tramadol was found to induce its anti-nociceptive effects
through monoamine neurotransmitters, whereas there was a cholinergic
component in the action of meptazinol[9]. For example,
the (-)-enantiomer of meptazinol was shown to be an inhibitor of
acetylcholinesterase in vitro with potency 100-fold less
than that of physostigmine[10]. All this evidence implies
that there would be a unique analgesic mechanism for meptazinol.
Therefore, we are very interested in exploring the analgesic mechanism
of meptazinol. Because the three-dimensional structures of opioid
receptors are not available yet, as a first step of exploration
we focused on structural comparisons of meptazinol with typical
opiates and with tramadol. Our results will help elucidate the analgesic
mechanism of meptazinol and will benefit the search for non-addictive
analgesics.
Materials and methods
All calculations were carried out on a R14000 SGI Fuel workstation
using the molecular modeling software package SYBYL version 6.9
(Tripos, St Louis, MO, USA).
Material preparation Both enantiomers of meptazinol were
synthesized in our laboratory. Their analgesic activities were determined
by observing the wrenching body reaction of mice after oral administration
at the Shanghai Institute of Materia Medica, Chinese Academy of
Sciences. Their absolute configurations were determined using x-ray
crystallography, co-crystallizing with dibenzoyl tartaric acid (DBTA),
in our previous work[11], which was used as a starting
point for this study. For each enantiomer of meptazinol, a random
search was carried out on the seven-member ring to ensure a stable
ring conformation. Then, all of the other rotatable bonds (except
bonds within the seven-member ring) were selected for a systematic
search with an interval of 30º for each bond to obtain the
lowest energy conformation. After the initial simple energy minimization,
the lowest energy conformation of meptazinol was further optimized
using a quantum chemical calculation [semi-empirical Austin Model
1 (AM1) method[12] available in SYBYL]. This final optimized
geometry of meptazinol was used in the subsequent structural comparisons.
Nine typical opiates, including agonists, antagonists and partial
agonists, were selected to generate the opioid pharmacophore according
to previous literature [13]. The initial atomic coordinates
for seven of these opiates (ie morphine[14], 3-O-methyletorphine[15],
azidomorphine[16], N-allynormetazocine[17],
cyclazocine[18], naloxone[19], and nalbuphine[20])
were obtained from published x-ray crystallographic data and modeled
using the CRYSIN tool of SYBYL. The other two opiates, codeine and
6-hydroxylevalorphan, were constructed based on their analogues,
the crystal structures of which were available in SYBYL.
The initial structure of (R,R)-tramadol, the active
isomer of tramadol, was retrieved from the MDL Drug Data Report-3D
database (MDDR-3D), and underwent a similar optimizing treatment
to meptazinol with one exception. All the rotatable bonds of tramadol
(except bonds within the six-member ring) underwent a genetic algorithm
conformational search to find the corresponding lowest energy conformation.
All structures were energy minimized for 1000 steps using the Tripos
force field and POWELL method and the termination setting was 0.001 kcal/(mol´A).
Analgesic pharmacophore generation The analgesic pharmacophore
is defined in Figure 2. For comparison, related values were obtained
from the literature[13] in which the pharmacophore was
composed of four distances and two torsion angles. We extracted
the common structures of nine opiates composed of a tyramine fragment
considered to be the key pharmacophore according to the average
values of the nine opiates. As shown in Figure 2, it should be noted
that the hydroxyl group was located in the para-position
of the phenyl ring in the opiates, but in the meta-position
of the phenyl ring in meptazinol and tramadol (methoxyl instead
of hydroxyl group in tramadol). Thus, we manually removed the two
carbons between the nitrogen atom and the phenyl ring from the pharmacophore
structure. The pharmacophore are composed of one protonated nitrogen
atom and a phenol fragment. We superimposed all opiates to the pharmacophore
template separately and calculated the average standard deviation
value as shown in Table 1. In addition, we defined the pharmacophore
for meptazinol and tramadol. One more torsion angle was defined
in tramadol because the interval distance between the nitrogen atom
and the phenyl ring is three carbon atoms in tramadol compared with
two in the other compounds.
Structural superposition The method used to determine superposition
was the database alignment facility in SYBYL, in which some or all
of the molecules in the database were aligned with a template molecule
also in the database. A common substructure was provided to evaluate
the best "fit". Only rigid-body rotations and translations
were supported.
For the comparison of meptazinol with the opioid pharmacophore,
the generated pharmacophore were set as the common substructure
for alignment. Both enantiomers of meptazinol were superimposed
on each other first, and then superimposed with the other opiates
separately.
Using the same pharmacophore, both meptazinol enantiomers and tramadol
were superimposed onto the template.
Results and Discussion
The analgesic activities were determined as ED50 values
for the two enantiomers of meptazinol, 14.583 µmol/kg for (+)-enantiomer
and 31.333 µmol/kg for the (-)-enantiomer. The (+)-enantiomer
is more potent than the (-)-enantiomer, although the difference
between them was not significant.
Because the structures of morphine and its derivatives and analogs
are fairly rigid, it is reasonable to assume that their x-ray structures
are the same as the active conformations binding to opioid receptors.
Therefore, our pharma-cophore model was based on these rigid structures.
According to the analgesic pharmacophore defined in Figure 2, we
built this pharmacophore using the mean values of the nine opiates
as the common substructure for superposition in SYBYL. For reasons
mentioned above, we removed the two carbon atoms from the pharmacophore.
We also measured the torsions of our pharmacophore structures without
the removal of the carbon atoms to make our pharmacophore resemble
the original one in the literature (Table 1).
The crystal structures of the meptazinol enantiomers were treated
with a series of methods to determine the lowest energy conformer
for each enantiomer. According to the systematic search results
for both meptazinol enantiomers, we found the lowest energy conformations
to be very similar. The lowest energy conformation was selected
as the low energy conformer followed by semi-empirical AM1 geometry
optimization.
Using the opiate pharmacophore as the overlap template we first
superimposed both enantiomers of meptazinol onto each other. As
illustrated in Figure 3, the pharmacophore elements of the meptazinol
enantiomers superimposed well onto each other. Thus, both meptazinol
enantiomers may induce a similar analgesic mechanism, at least in
part. An experiment using electrical stimulation of guinea pig isolated
ileum indicated that both enantiomers of meptazinol were µ-selective
opioid receptor agonists[21]. And the similar pharmacology
results from observing the mice wrenching body reaction of meptazinol
enantiomers also supports this conclusion, although for the (-)-enantiomer
there is another cholinergic component in the participating antinociceptive
effect[10].
However, as demonstrated in Figure 4, the meptazinol pharmacophore
differed from the opiate pharmacophore, particularly in the position
of the nitrogen atom. The overlap of (+)-meptazinol to the opiate
pharmacophore is a little better than (-)-meptazinol in the region
of the phenol fragment, which may account for the minor increase
in analgesic effect of (+)-meptazinol. These differences were also
reflected in related molecular parameters. From Table 1, we can
see that distance A in the pharmacophore of meptazinol was about
0.6 Å shorter than that in the opiates examined. The
nitrogen atom actually becomes further away (>0.7 Å)
from the phenol fragment in meptazinol than in the opiates, which
was confirmed by the increased B and D values in meptazinol. Both
enantiomers of meptazinol did not fit the skeletons of the opiates
particularly well. The azepane ring of meptazinol did not match
the corresponding alkyl chain between the nitrogen atom and the
phenol fragment in the opiates (Figure 4). Whether or not the azepane
ring contributes to analgesic potency needs further investigation.
In addition, we compared meptazinol with tramadol because they
share more common pharmacological effects with each other than with
other opiates. It should be noted that we still used the pharmacophore
model generated from the opiate structures because their pharmacology
may be mediated by a similar mechanism. To determine the active
conformation of (R,R)-tramadol, a series of methods
were carried out. Twenty-four minimum energy conformations of tramadol
were analyzed and found to be very similar to each other. Therefore,
the lowest energy conformation was selected and geometrically optimized
further using the quantum chemical calculation method AM1, which
resulted in the active conformation of tramadol. The related molecular
parameters of tramadol are also listed in Table 1, and the superposition
of tramadol with meptazinol is shown in Figure 5. Although the pharmacophore
of meptazinol enantiomers and tramadol occupied a similar region,
poor overlap occurred between meptazinol enantiomers and tramadol
in the phenol fragment and the protonated nitrogen atom. Although
(R,R)-tramadol shares some similar pharmacological
effects with meptazinol, our studies revealed that their pharmacophores
might be different.
Conclusion
In summary, from the structural comparisons conducted in the present
study we learned that both enantiomers of meptazinol differed from
typical opiates and from (R,R)-tramadol. However,
the pharmacophore of both enantiomers of meptazinol might be similar
to each other, and this result is consistent with previous studies[21].
Therefore, we suggest that meptazinol has a unique analgesic mechanism
that is different from known analgesics (ie meptazinol may not target
opioid receptors only, and one of its enantiomers might act on other
targets in the cholinergic system). The antinociceptive targets
and mechanism of meptazinol enantiomers needs to be investigated
further.
Acknowledgements
We thank researchers from the Shanghai Institute of Materia Medica,
Chinese Academy of Sciences for the pharmacological test of the
meptazinol enantiomers.
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