Might adrenergic α2C-agonists/α2A- antagonists become novel therapeutic tools for pain treatment with morphine?

Article abstract of DOI:10.1021/jm901262f

The imidazoline nucleus linked in position 2 via an oxyethylene bridge to a phenyl ring carrying an ortho substituent of moderate steric bulk provided α2-adrenergic (AR) ligands endowed with significant α_2C- agonism/α_2A-antagonism. S

Full text of DOI:10.1021/jm901262f

J. Med. Chem. 2009, 52, 7319–7322 7319
DOI: 10.1021/jm901262f
Might Adrenergic r2C-Agonists/r2A-Antagonists Become Novel Therapeutic Tools for
Pain Treatment with Morphine?1
Claudia Cardinaletti,† Laura Mattioli,‡ Francesca Ghelfi,† Fabio Del Bello,† Mario Giannella,† Ariana Bruzzone,§
‡
†
†
Herve Paris, Marina Perfumi, Alessandro Piergentili, Wilma Quaglia, and Maria Pigini*
,†
ꢀ
†Dipartimento di Scienze Chimiche, Universitaꢁ degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino, Italy,
‡Dipartimento di Medicina Sperimentale e Sanitaꢁ Pubblica, Universitaꢁ degli Studi di Camerino, Via Madonna delle Carceri,
§
62032 Camerino, Italy, Instituto de Biologıa y Medicina Experimental, CONICET, Obligado 2490, C1428ADN Buenos Aires,
´
Argentina, and INSERM Uniteꢀ 858, I2MR, Bat L3, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France
Received September 4, 2009
The imidazoline nucleus linked in position 2 via an oxyethylene bridge to a phenyl ring carrying an ortho
substituent of moderate steric bulk provided R2-adrenergic (AR) ligands endowed with significant
R
2C-agonism/R2A-antagonism. Similar behavior was displayed by cirazoline (12). For their positive
morphine analgesia modulation (due to R2C-AR stimulation) and sedation overcoming (due to R2A-AR
antagonism), 8 and 11 might be useful as adjuvant agents in the management of pain with morphine.
Chart 1. Imidazoline Molecules Interacting with R2-ARs and
I2-IBS (1), R2-ARs (2, 5, 8-14), I2-IBS (3, 6), and I1-IBS (4, 7)
Introduction
R2-Adrenoreceptors (R2-ARsa) consist of three subtypes
( R2A, R2B, and R2C)2 and are considered attractive therapeutic
targets. Studies of mice lacking or overexpressing R2-AR
subtypes3 demonstrated that the R2A-AR subtype mediates
hypotension, sedation, analgesia, while the R2B subtype med-
iates hypertension. The R2C-AR subtype appears involved in
many CNS processes and proves to contribute to adrenergic
opioid synergy and spinal R2-agonist-mediated analgesia.4 It
is known that imidazoline derivatives may interact with
R-ARs and imidazoline binding sites (I1-, I2-IBS).5 Our
experience highlighted that the two groups, the bridge
X and the aromatic area Ar forming the substituent in
position 2 of the imidazoline nucleus (Chart 1), displayed
different functions. Indeed, minor chemical modifications to
thebridgedetermined the preferential recognitionbya specific
biological system,6 whereas those in the aromatic region
sometimes induced subtype-selective interaction but always
caused decisive modulation of the ligand functional beha-
vior.7 In summary, the oxymethylene bridge (1) appeared
favorable for R2-ARs and I2-IBS. Additionally, 1 demon-
strated antagonist and agonist properties at R2- and R1-ARs,
respectively. The methyl group in the bridge (2) improved the
R2-AR antagonist potency, slightly lowered R1-AR intrinsic
activity, and drastically reduced the I2-IBS affinity.6,8 The R2-
AR specificity of 2 was favored by the recognition of a
lipophilic cavity, named “methyl pocket”.9 In a different
manner, the wholly carbon nature of the bridge favored IBS
selectivity: 3 (phenyzoline) and 4 proved effective for I2- or
I1-IBS, respectively.6 Moreover, in the case of R2-AR ligands,7
we demonstrated that chemical modifications in the Ar group,
such as the introduction of an ortho phenyl substituent
into the aromatic ring of the nonsubtype selective R2-AR
antagonist 2 caused an important modulation of receptor
interactions. The antinociceptive R2A- and R2C-AR agonist
biphenyline (5) was thus obtained.8,10 Unambiguously, from
comparative examination of several compounds some signi-
ficant analogies between binding site cavity of R2-ARs and
IBS emerged. Indeed, the insertion of the ortho phenyl group
turned the biological profile of 3 from positive to negative
modulator (6, diphenyzoline) of morphine analgesia;11 ana-
logously, the antagonist 4 changed into the antihyperten-
sive agonist 7.12 Interestingly, concerning R2-AR ligands, we
observed that the ortho allyl substituent of moderate steric
bulk (MR = 14.49)13 modulated the biological profile of the
antagonist 2 only at R2C-AR.7 Indeed, at this subtype 8
showed good intrinsic activity and high potency, whereas it
displayed the same antagonist character of its prototype 2
at the R2A-subtype (Table 1). This observation highlighted
the possibility of obtaining novel R2-AR agonists, with the
potential to evoke the physiological responses mediated by
R
2C-AR subtype without having the side effects associated
*To whom correspondence should be addressed. Phone: þ39 0737
402257. Fax: þ39 0737 637345. E-mail: maria.pigini@unicam.it.
a Abbreviations: IBS, imidazoline binding sites; R2-ARs, R2-adreno-
receptors; (-)-NA, (-)-noradrenaline; MR, molar refraction; CHO,
Chinese hamster ovary; DME, 1,2-dimethoxyethane; MPE, maximum
possible effect.
with R2A-AR stimulation. To confirm this result, we prepared
and studied some analogues of 8 (9-11). Similar to allyl, the
methyl (MR = 5.65) (9), n-propyl (MR = 14.96) (10), and
cyclopropyl (MR = 13.53) (11) pendent groups were endowed
r
2009 American Chemical Society
Published on Web 11/03/2009
pubs.acs.org/jmc

7320 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22
Cardinaletti et al.
Table 1. Affinity (pKi a), Antagonist Potency (pKb b), Agonist Potency (pEC50 b), and Intrinsic Activity (iab) on Human R2-AR Subtypes
R2A
R2B
R2C
compd
pKi
pEC50 (pKb)
ia
pKi
pEC50 (pKb)
ia
pKi
pEC50 (pKb)
ia
2
7.57 ( 0.09
7.24 ( 0.11
7.61 ( 0.14
7.30 ( 0.11
7.64 ( 0.20
7.23 ( 0.10
7.46 ( 0.10
7.31 ( 0.11
(7.01 ( 0.10)
(7.40 ( 0.06)
(7.51 ( 0.08)
(7.05 ( 0.20)
(7.00 ( 0.09)
(6.40 ( 0.12)
(6.54 ( 0.16)
(6.28 ( 0.06)
6.43 ( 0.17
6.78 ( 0.13
6.47 ( 0.20
6.57 ( 0.20
6.27 ( 0.15
6.51 ( 0.13
6.28 ( 0.14
6.40 ( 0.09
6.26 ( 0.20
(6.20 ( 0.18)
na
6.58 ( 0.12
7.07 ( 0.14
6.57 ( 0.12
6.83 ( 0.21
7.10 ( 0.16
6.26 ( 0.15
6.30 ( 0.13
6.31 ( 0.14
(6.85 ( 0.15)
7.30 ( 0.09
7.20 ( 0.12
7.60 ( 0.18
7.40 ( 0.13
6.40 ( 0.10
5.54 ( 0.20
6.81 ( 0.09
6.10 ( 0.05
8
0.90
0.67
0.75
0.90
0.80
0.50
0.90
1.00
9
10
6.00 ( 0.22
5.30 ( 0.12
5.50 ( 0.15
6.00 ( 0.13
6.00 ( 0.13
5.60 ( 0.09
7.21 ( 0.25
0.40
0.60
0.70
1.00
0.70
0.70
1.00
11
12
13
14
(-)-NA
1.00
a pKi values were calculated from [3H]RX 821002 on membrane preparations from CHO cells expressing individually each human R2-AR subtype
(R2A, R2B, R2C). b pKb, pEC50, and intrinsic activity (ia) values were determined by applying the Cytosensor microphysiometry system to the same cell
models. Intrinsic activityof the tested compounds is expressed as the fraction of that of the full agonist (-)-NA taken as equal to 1. The data are expressed
as the mean ( SEM of three to six separate experiments. Compounds exhibiting ia of <0.3 were considered not active (na).
Scheme 1a
(pEC50 = 6.00, ia = 1.00) (Figure 1). 13 and 14, the desmethyl
analogues of 9 and 10, respectively, showed similar profiles.
The higher potency values of 8-11 at R2C-subtype were
probably favored by the presence of the methyl group in the
bridge. To further delineate their functional behavior, 9-14
were tested for their capacity to cause receptor-mediated
Erk phosphorylation. Compared to the positive control
(-)-NA, 12 (Figure 1) and all the other compounds had only
marginal incidence on Erk phosphorylation in cells expressing
a Reagents and conditions: (a) methyl 2-bromopropionate, K2CO3;
(b) (CH3)3Al, dry toluene, ethylenediamine, Δ.
the R2A-subtype but increased it in cells expressing R2B
-
with moderate steric bulk. The corresponding desmethyl
analogues 12-14 were included in this study. The pharma-
cological profiles were evaluated by binding and functional
studies on CHO cells expressing recombinant human R2-AR
and R1-AR subtypes. 9, 13, and 14, already known,5 and 10,14
cited but not previously described, have never been studied
from this point of view. Selected compounds were also
evaluated on algesiometric and sedation tests.
or R2C-subtype. The R1A-AR pKi affinity values of 8-14
ranged between 6 and 6.9, but as expected,8,9 from func-
tional studies 8-11 showed low intrinsic activity (ia < 0.3),
whereas 12 and the other desmethyl analogues 13 and 14
activated this receptor (for 12, pEC50 = 7.00, ia = 0.6;
for 13, pEC50 = 6.49, ia = 0.7; for 14, pEC50 = 6.80, ia =
0.9). Moreover, 8-14 displayed poor affinities (pKi < 5)
at R1B- and R1D-AR subtypes. As known, some nonsubtype
selective R2-agonists, such as clonidine, tizanidine, and bri-
monidine, are used as primary analgesics16 and adjuvant
analgesics in synergic combination with opioids.17 Neverthe-
less, in systemic long-term use their side effects, associated
with R2A-activation, limit their therapeutic potential. There-
fore, with the hope of exploring an alternative avenue to
known opioids and non-opioids in combination management
and obtaining the separation of the analgesic from side effects,
we evaluated in vivo the behavior of some of our molecules.
Morphine analgesia modulation and analgesia effects pro-
duced by 8, 11, and 12 and sedation effects produced
by 8 and 11 were determined. Clonidine was included as
reference compound. 8, 11, and 12 caused a significant
increase in morphine analgesia (Figure 2), since augmented
tail-flick latency was still observed 120 min after administra-
tion. Of note the lowest dose of 8 or 11 (0.05 mg/kg) caused an
effect comparable to that obtained with a 0.5 mg/kg dose of 12
or clonidine. At lower doses (<0.5 mg/kg) clonidine or 12 did
not affect morphine analgesia; the higher doses required for
these compounds might be due to their R1A-AR activation,
which can counterbalance their R2-AR-induced effects.16-18
Moreover, on the basis of the considerations reported in
the Introduction, the I2-IBS affinity (pKi = 7.90)5 due to
the oxymethylene bridge6 and the ortho substituent of the
aromatic ring might confer on 12 some negative modulatory
properties11 and weaken its R2C-AR-mediated morphine
analgesia enhancement. Anyway, the potentiation of opiod-
evoked analgesia displayed by 8 and 11 confirmed the pre-
vious results obtained from genetically engineered mice.4
Chemistry
9, 13, and 14 were prepared as previously reported.5 Con-
densation of the suitable phenols with methyl 2-bromopro-
pionate afforded the esters 15 and 16, which by treatment with
ethylenediamine in the presence of (CH3)3Al gave 10 and 11
(Scheme 1).
Results and Discussion
From the data reported in Table 1, it emerged that at
the three different R2-AR subtypes, 9-11 showed binding
affinities comparable to those of their precursor 2. However,
as assessed by a Cytosensor microphysiometry,7 analogous
to lead 8, they displayed good intrinsic activity and remark-
able potency at R2C-subtype (for 9, pEC50 = 7.20, ia = 0.67;
for 10, pEC50 = 7.60, ia = 0.75; for 11, pEC50 = 7.40, ia =
0.90). The R2B-AR potencies were found to be significantly
lower. The lack of R2A-AR agonism and the good R2A-AR
affinity of 9-11 prompted us to evaluate their antagonist
properties at this subtype. As expected, similar to the lead 8,7
9-11 displayed the same antagonist character as2 (pKb R2A of
7.51, 7.05, and 7.00, respectively). Since the recognition of the
“methyl binding pocket” alone did not induce R2-AR agonist
activity,8 the promising R2C-AR agonism of 11, which may
be regarded as the methyl derivative of cirazoline (12),
prompted us to re-examine the pharmacological profile of
12, so far considered as an R2-AR antagonist.15 As expected,
12 behaved as antagonist at R2A-subtype (pKb = 6.40) and as
agonist at R2C- (pEC50 = 6.40, ia = 0.80) and R2B-subtypes

Brief Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22 7321
Figure 1. Stimulation of extracellular acidification in CHO cells stably expressing the human R2C- (A) and R2B-AR subtypes (B) by (-)-NA (9)
and 12 (2) and R2A-AR subtype (C) by clonidine (9), 12 (2), and 12 (1 μM) with clonidine (b). Data points with error bars represent the mean (
SEM of three to six separate experiments. Levels of Erk phosphorylation are produced by 12 and (-)-NA on CHO cells expressing R2C- (A0),
R
2B- (B0), and R2A-AR subtypes (C0). Phosphorylated Erk (ErkP) and total Erk (Erk) were revealed by Western blotting with specific
antibodies.
Figure 2. Effects of clonidine and cirazoline (A), 8 (B), and 11 (C) on morphine analgesia in the tail-flick test. The reaction latencies were
expressed as a percent of the maximum possible effect (% MPE). Each point represents the mean ( SEM of six to eight animals. Significant
differences are as follows: (/) p < 0.05, (//) p < 0.01 compared to morphine treated group. Where not indicated, the difference was not
statistically significant.
In addition, the R2-AR activation was unambiguously
demonstrated by the observation that the effects of 8 and 11
were blocked by pretreatment with the R2-AR antagonist
yohimbine (Supporting Information Figure S1). 8 was devoid
ofantinociceptiveproperties, whereas11exhibiteda weakand
dose-dependent analgesic effect (Supporting Information
Figure S2). Finally, in agreement with the expected lack of
sedation, at doses producing significant potentiation of the
analgesic effect of morphine, 8 and 11 did not increase the
sleeping time induced by pentobarbital; in contrast, a 5- and
Figure 3. Effects of 8, 11, and clonidine on pentobarbital-induced
sleeping time. The time between losing and regaining righting reflex
6.6-fold increase of sleeping time was caused by clonidine and
diazepam administration, respectively (Figure 3). In conclu-
was considered as the duration of sleep time (min): (//) p < 0.01
sion, the present research (i) strengthened our convinction
compared to vehicle.
that R2-AR specificity, functional behavior, and subtype
selectivity of imidazoline molecules were determined by the
peculiar nature of the X and Ar fractions of the substituent in
position 2 of the imidazoline ring, (ii) demonstrated that the
simultaneous presence of an oxyethylene bridge and ortho
substituent of moderate steric size in the Ar fraction induced
preferential R2C-activation, (iii) allowed us to further char-
acterize the biological profile of cirazoline, and finally,
(iv) suggested that given their ability to positively modulate
morphine analgesia (due to R2C-AR stimulation) and to
overcome sedation (due to R2A-AR antagonism), 8 and 11

7322 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22
Cardinaletti et al.
merit further investigation as novel and suitable adjuvants in
the management of pain with opioids. The present results and
the stereospecific requirements of R2-ARs prompt us to
prepare and study the enantiomers of 8 and 11.
(2) Hieble, J. P. Subclassification and nomenclature of R- and
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Experimental Section
The purity of the new compounds was determined by combus-
tion analysis and was g95%.
2-(2-Propylphenoxy)propionic Acid Methyl Ester (15). A mix-
ture of 2-propylphenol (0.26 g, 1.93 mmol), methyl 2-bromo-
propionate (0.22 mL, 1.93 mmol), and K2CO3 (0.27 g, 1.93
mmol) in DME was refluxed for 8 h. The mixture was filtered,
and the solvent was removed. The residue was taken up in
CH2Cl2 and washed with 2 N NaOH. Removal of the solvent
afforded an oil which was purified by flash cromatography
(cyclohexane/EtOAc, 9/1) (0.25 g, 59% yield). 1H NMR
(CDCl3) δ 0.95 (t, 3, CH2CH3), 1.62 (d, 3, CHCH3), 1.64
(m, 2, CH2), 2.67 (t, 2, CH2), 3.73 (s, 3, OCH3), 4.78 (q, 1,
OCH), 6.65-7.18 (m, 4, ArH).
2-(2-Cyclopropylphenoxy)propionic Acid Methyl Ester (16).
Similarly, 16 was obtained from 2-cyclopropylphenol. Yield,
75%. 1H NMR (CDCl3) δ 0.57-1.02 (m, 4, CH2CH2), 1.67 (d, 3,
CHCH3), 2.26 (m, 1, CH), 3.78 (s, 3, OCH3), 4.78 (m, 1, OCH),
6.62-7.12 (m, 4, ArH).
2-[1-(2-Cyclopropylphenoxy)ethyl]-4,5-dihydro-1H-imidazole
(11). A solution of ethylenediamine (0.42 mL, 6.28 mmol) in dry
toluene (6 mL) was added dropwise to a mechanically stirred
solution of 2 M (CH3)3Al (3.2 mL, 6.28 mmol) in dry toluene
(4 mL) at 0 °C under a nitrogen atmosphere. After the mixture
was stirred at room temperature for 1 h, a solution of 16 (0.69 g,
3.14 mmol) in dry toluene (8 mL) was added dropwise. The
mixture was heated to 110 °C for 3 h, cooled to 0 °C, and
quenched with MeOH (0.8 mL) followed by H2O (0.2 mL) and
CHCl3 (5 mL). The mixture was filtered and extracted with 2 N
HCl. The aqueous layer was made basic with 10% NaOH and
extracted with CHCl3. The oil residue was purified by flash
chromatography (cyclohexane/EtOAc/MeOH/33% NH4OH,
6/4/1/0.1). The free base (63% yield) was transformed into the
hydrogen oxalate salt and recrystallized from EtOH: mp
141-142 °C; 1H NMR (DMSO) δ 0.51-0.98 (m, 4, CH2CH2),
1.58 (d, 3, CHCH3), 2.24 (m, 1, CH), 3.91 (s, 4, NCH2CH2N),
5.37 (q, 1, OCH), 6.83-7.18 (m, 4, ArH), 9.51 (br s, 1, NH,
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exchangeable with D2O). Anal. (C14H18N2O H2C2O4) C, H, N.
3
2-[1-(2-Propylphenoxy)ethyl]-4,5-dihydro-1H-imidazole (10).
Similarly, 10 was obtained from 15. Yield, 65%. Recrystalliza-
tion was from EtOH/Et2O: mp 145.2-145.9 °C; 1H NMR
(DMSO) δ 0.95 (t, 3, CH2CH3), 1.68 (d, 3, CHCH3), 1.60
(m, 2, CH2), 2.67 (t, 2, CH2), 3.85 (m, 4, NCH2CH2N), 5.38
(14) Baganz, H.; May, H. J. Antihypertonic 2-(1-Aryloxyethyl)-2-imi-
dazolines. Ger. Offen 1,695,555, 1971; Chem. Abstr. 74, 87979.
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activity of clinical R-adrenergic receptor agonists interferes with
R-2-mediated analgesia. Anesthesiology 2009, 110, 401–407 and
references therein.
(q, 1, OCH), δ 6.85-7.20 (m, 4, ArH). Anal. (C14H20N2O
H2C2O4) C, H, N.
3
Supporting Information Available: Chemical methodology,
biological experiments, and elemental analysis results. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(17) Gulati, A.; Bhalla, S.; Matwyshyn, G.; Zhang, Z.; Andurkar, S. V.
Determination of adrenergic and imidazoline receptor involvement
in augmentation of morphine and oxycodone analgesia by cloni-
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therein.
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