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Introduction
Meptazinol [its (+)-isomer is shown in Figure 1] is an opioid with similar analgesic activity to pethidine (also known as
meperidine). Since it entered into the market in the 1980s as a racemic mixture, it has been recognized and recommended as a
mixed agonist-antagonist opioid[1]. It was found to antagonize morphine induced physical
dependence in vivo[2], however, its analgesic mechanism remains unclear. For a long time meptazinol was suggested to perform its analgesic function through
the m1 opioid receptor[3], which was believed to mediate analgesia while reducing the addition and respiratory depression
potential.
In our previous studies, the X-ray determined enatiomers
of meptazinol were compared with typical µ opiate
pharma-cophore, but they failed to fit that pharmacophore
well[4]. Meanwhile, during the investigation of (+)-meptazinol hydrochloride in
solution, two conformers (Conformer-I and -II; Figure 1) were elucidated with NMR spectroscopy, in which the phenyl group
of meptazinol could take ax- or eq- orientations, respectively, to the azepine ring. Conformer-II was very similar to
Conformer-III (Figure 1), which was determined by X-ray crystallography. Here only the two NMR conformers of (+)-meptazinol were
discussed. It is worthy to note that the relative quantity of the two conformers in solution were almost the same amount
(approximately 3:2),
although their calculated energy was somewhat different (Table 1).
As Conformer-III (very similar to Conformer-II) failed to fit the typical opiate
pharmacophore[4], it was reasonable to consider that Conformer-I, with higher energy, was the bio-active conformer while Conformer-II (or Conformer-III) was
inactive. After all, a conformer with the lowest energy is not always the biological active conformer for a compound with
certain biological activities.
In this study, two typical pharmacophores from different opioids were established and validated. And both conformers
of (+)-meptazinol were used for structural comparisons to analyze their specific properties. This study provides new insights
into understanding the nature of mixed pharmacophores to (+)-meptazinol and the complicated pharmacology of meptazinol.
Materials and methods
Material preparation 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).
The initial pharmacophore of morphine analogs were modeled in our previously published
paper[4]. The conformer of meperidine was well examined by X-ray
crystallographic[5] and
NMR[6] techniques and thus was modeled according to literature.
The two different conformers of (+)-meptazinol (Conformer-I and -II) were obtained by molecular dynamics from NOESY and
TOCSY spectra. Several conformationally constrained aromatic substituted
piperidines[6_11] were sketched in SYBYL
according to the reported preferred conformers with all basic nitrogen atoms protonated. The initial structures were firstly minimized
by Tripos force field with Gasteiger-Huckel charges, followed by random searches to ensure their stable conformations by
default settings. Finally, all structures were optimized with the semi-empirical quantum chemical method Austin Model 1
(AM1; available in
SYBYL)[12], and the geometrically optimized structures were used for further structural comparisons.
Establishment and validation of two opioid pharmaco-phores Two opioid pharmacophores, namely Pharm-I and -II, were
defined from structures of nine typical opiates and meperidine, separately, (Figure 2a and 3a). Each pharma-cophore contains
one aromatic region (defined by the center of phenyl rings), one cation center and a hinge atom. In addition, two distance and
one angle parameter were also calculated to constrain these components' distribution in space (Table 2). Pharm-I was
modeled from the mean values of nine typical opiates (Figure 2b). And the root mean square deviations (RMSD) fitting values
of nine opiates were listed in Table 3. Pharm-II was extracted from the well-established meperidine conformer (Figure 3b).
With the defined pharmacophores, all structural comparisons were made by Fit Atoms facilities available in SYBYL. And
the established pharmacophores were validated by fitting a set of constrained arylpiperidines (Table 4).
Fitting conformers of (+)-meptazinol to the pharmaco-phores Both Conformer-I and -II of (+)-meptazinol were fitted into
both opioid pharmacophores separately to see if they share similar properties. Furthermore, both conformers
were superimposed with the structure of compound-4 (Table 5).
Results
and discussion
Establishment and validation of opioid
pharmacophores It was suggested that arylpiperidines and structural related
analgesics could be divided into two categories according to the orientation of the aryl
group[13]: ax- and eq- phenyl models.
The prototype analgesics of ax- and eq- phenyl models were morphine and meperidine, respectively. And arylpiperidines
with phenyl ax-conformer could also be
classified as ax- phenyl models not only for similar phenyl orientation but also for similar structure activity relationships.
Although there was evidence that analgesics in these categories were both µ opioid
ligands[14], these two models bear different structure activity relationships properties based on the following facts: 1) N-allyl or cyclopropyl methyl analogs in ax- phenyl conformers induced antagonist activity, but those in eq- phenyl conformers did
not[13]; 2) introduction of a 3R-methyl group into the piperidine ring in analogs
of eq- phenyl conformers mediates pure antagonist
potency[15] but not in those of ax- phenyl conformers; 3) in reversed esters of meperidine with preferred eq- phenyl conformers, phenolic hydroxyl insertion virtually abolishes
activity[16,17]. However, in most other analogs, an m-placed phenolic hydroxyl group enhances analgesic activity. The major structural difference between these two categories was the different orientations of their aryl
groups which mainly account for different pharmacological properties. Thus Portoghese et al proposed different binding models to
m opioid receptor for compounds in these
categories[16].
Here, typical opioids of ax-phenyl (nine opiates) and eq-phenyl (meperidine) were used to establish their corresponding
pharmacophores. Although the tyramine fragment was widely used as typical opioid pharmacophore in the published
literature[18] as well as in our previous
studies[4], the phenyl ring of ax- arylpiperidines actually bears a relationship
orthogonal to that obtained in the rigid skeleton of
morphine[19,20]. Thus not only the phenyl plane but also the hydroxyl group on the
aromatic ring between opiates and ax- arylpiperidines were quite different. Superimposing
ax- arylpiperidines to morphine derived tyramine fragments will lead to poor overlaps. Considering phenyl groups could form
either parallel or T-shape p-p interactions with the hydrophobic site, and hydroxyl groups in a given region could also interact
with the hydrogen acceptor on the receptor, it seemed unnecessary to consider the overall fit between the phenolic groups
between ax- arylpiperidine and opiates. Here, we excised the tyramine fragment down to an aromatic center, a cation center
and a hinge atom connecting piperidine and phenyl rings to unify these structurally diverse opioids with ax- phenyl conformers. The hydroxyl group was excluded from our pharmacophore not only for its
ambiguous function in arylpiperidines, but for poor fitting
results among different analgesics, although it was also used for structural reference in this study. The relative orientation
of the phenyl ring toward the piperidine group could be simply determined by the angle values defined in Table 2.
Common model definitions for these two pharmacophores were as follows: 1) The center of aryl rings to form hydrophobic
interactions with the opioid receptor; 2) the protonated nitrogen atom to form salt bridges with anion center on the receptor;
3) the hinge atom that held the relative orientation of phenyl to piperidine ring. Although the two pharmacophores shared
similar distance parameters (Table 2), the angle parameters were quite different. The angle was
107.54º in Pharm-I (with ax- phenyl conformer) and
151.8º in Pharm-II (with eq- phenyl conformer), which could also be regarded as the main difference
between the two pharmaco-phores.
Some typical constrained arylpiperidines with known potent analgesic potencies were used for validation of the modeled
pharmacophores. And all of these compounds could be identified to their correct pharmacophores by RMSD fitting values
below 0.2Å, as well as by determining their phenyl orientations except for compound-1 and 4. Although compound-1 took ax- phenyl conformer, it seemed more reasonable to be classified to Pharm-II because the framework of the tropane ring
constrained the relative position of the defined three components to Pharm-II (with eq- phenyl conformer). However, compound 4 could be classified to neither Pharm-I nor Pharm-II and its special pharmacophore will be discussed in the next section of
this paper, although its phenyl ring took eq- conformer.
Structural comparison of (+)-meptazinol with opioid pharmacophores As a ring expanded the analog of 4-arylpiperidine,
both (+)-meptazinol conformers were fitted to the established opioid pharmacophores. Conformer-I was found to fit
Pharm-I well but not Pharm-II (Figure 2c and Table 5).
However, Conformer-II fit none of these pharmacophores (Table 5). Similar conclusions were made in our previous
studies based on tyramine fragment derived opiate
pharmacophore[4]. Furthermore, Conformer-II was energy favored with
calculated energy 3.651 kcal/mol lower than Conformer-I. Should Conformer-II also be considered as an inactive conformer?
Surprisingly, conformer-II showed similar fitting values to both pharmacophores (0.424 for Pharm-I and 0.289 for
Pharm-II) as compound-4 (0.390 for Pharm-I and 0.297 for Pharm-II), although they fit neither pharmacophore (Table 4 and Table 5).
Limited studies were carried out on these
analogs[10,11], but compound-4 was a potent µ opioid agonist. Another question
raised was whether these two structures shared similar properties. Considering its rigid structure and potency,
compound-4 could also be employed as an eligible template for structural comparison. With the same components of pharmacophore
defined previously, fitting Conformer-II to compound-4 led to good overlap results with a RMSD value of 0.182 (Figure 3c and
Table 5).
In addition, the angle parameter of compound-4 was
129.50º, a halfway transition state between Pharm-I and -II (Figure 3d). And it was
136.56º for Conformer-II of (+)-meptazinol.
Typical arylpiperidines generally took Pharm-I
(ax- phenyl) or Pharm-II (eq- phenyl) conformers to avoid disfavored steric
clashes. But the furan ring constrained compound-4 took such a distorted conformer that it belonged to neither of these two
conformers. Instead, it held a transition conformer between the two conformers. Considering other arylpiperidines with ring
constrains lacked analgesic
potencies[21], compound-4 may display specific pharmacological properties other than Pharm-I
and -II. Though conformer-II of (+)-meptazinol failed to fit Pharm-I and Pharm-II, it fit compound-4 well. So conformer-II was
also suggested to be an active conformer as analgesics.
Although both conformers of (+)-meptazinol were suggested to be active conformers against the µ opioid receptor, their
pharmacophores were different to each other. Conformer-I was suggested to fit typical opiate pharmacophore (Pharm-I) and
conformer-II shared similar properties with
benzofuro[2,3-c]pyridin-6-ol analogs. These conformers exist in similar amounts
in solution and could not transform to each other freely in ordinary conditions. Although it is also possible that
(-)-meptazinol may also account for analgesics and reduced side-effects as meptazinol was marketed as a racemic mixture. The
existence of multiple analgesic mechanisms in (+)-meptazinol may provide further insight into meptazinol's complex
pharmacological behavior.
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