Exploring multitarget interactions to reduce opiate withdrawal syndrome and psychiatric comorbidity

Article abstract of DOI:10.1021/ml400232p

Opioid addiction is often characterized as a chronic relapsing condition due to the severe somatic and behavioral signs, associated with depressive disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major challenge, our intere

Full text of DOI:10.1021/ml400232p

Letter
pubs.acs.org/acsmedchemlett
Exploring Multitarget Interactions to Reduce Opiate Withdrawal
Syndrome and Psychiatric Comorbidity
Fabio Del Bello,† Eleonora Diamanti,† Mario Giannella,† Valerio Mammoli,† Laura Mattioli,‡
Federica Titomanlio,‡ Alessandro Piergentili,† Wilma Quaglia,† Marco Lanza,§ Chiara Sabatini,§
Gianfranco Caselli,§ Elena Poggesi,∥ and Maria Pigini*,†
†School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Via S. Agostino 1, 62032 Camerino, Italy
‡School of Pharmacy, Pharmacognosy Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy
§Pharmacology & Toxicology Department, Rottapharm-Madaus, 20052 Monza, Italy
∥Recordati S.pA., Drug Discovery, Via Civitali 1, 20148 Milano, Italy
S
* Supporting Information
ABSTRACT: Opioid addiction is often characterized as a chronic relapsing
condition due to the severe somatic and behavioral signs, associated with depressive
disorders, triggered by opiate withdrawal. Since prolonged abstinence remains a major
challenge, our interest has been addressed to such objective. Exploring multitarget
interactions, the present investigation suggests that 3 or its (S)-enantiomer and 4,
endowed with effective α2C-AR agonism/α2A-AR antagonism/5-HT1A-R agonism, or 7
and 9−11 producing efficacious α2C-AR agonism/α2A-AR antagonism/I2−IBS
interaction might represent novel multifunctional tools potentially useful for reducing
withdrawal syndrome and associated depression. Such agents, lacking in sedative side
effects due to their α2A-AR antagonism, might afford an improvement over current
therapies with clonidine-like drugs.
KEYWORDS: α2-Adrenergic ligands, 5-HT1A agonists, I2−IBS ligands, morphine withdrawal symptoms reduction,
antidepressant-like effect
contribute to adrenergic-opioid synergy. In the brain, α2A- and
pioid exposure is known to induce potent analgesic effect
Oas well as relaxation and euphoria. The repeated use of α2C-ARs, as “heteroreceptors”, inhibit dopamine and serotonin
release.3−5 The nonsubtype selective α2-AR agonist clonidine
opiate drugs, both for the relief of chronic or cancer-related
has been clinically used alone or in combination with traditional
treatments for relief of withdrawal symptoms during detox-
ification, thus increasing treatment duration. Nevertheless,
clonidine, due to its α2A-AR subtype activation, is responsible
for side effects of sedation and hypotension,1 that limit the use
of high doses. Strong association between protracted abstinence
and depressive disorders, contributing to relapse, emerges from
epidemiologic retrospective studies, and adjunct antidepres-
sants are often included in the traditional treatments.1,6,7
Therefore, since prolonged abstinence remains a major
challenge, strategies addressed to discover multifunctional
agents that ameliorate withdrawal symptoms and relieve
depressive disorders should be explored. Recently,8,9 we
reported that allyphenyline (1) and cyclomethyline (2)
(Chart 1), devoid of sedative side effects, were able at the
same low dose (0.05 mg/kg) to significantly decrease the
naloxone-precipitated withdrawal syndrome and to exert a
pain and for recreational drug-taking behavior, can lead to the
development of dependence. Addiction to opioids is a complex
syndrome involving tolerance, drug-seeking, and physical
dependence with withdrawal avoidance behaviors. It is often
characterized as a chronic relapsing condition and is a major
health and social issue in most societies.1 Detoxification, a
necessary step for many forms of long-term abstinence-based
treatments, makes use of two approaches: tapering using
methadone or buprenorphine, or abrupt termination of opioid
use, potentially precipitated by an opioid antagonist (i.e.,
naltrexone) with administration of α2-adrenoreceptor (α2-AR)
agonists to reduce withdrawal symptoms.1 α2-ARs have been
demonstrated to be extremely sensitive to opioid exposure.2
Subdivided into α2A-, α2B-, and α2C-subtypes, α2-ARs belong to
the superfamily of G-protein-coupled receptors and are widely
distributed in the central nervous system (CNS) and in
peripheral tissues.3 The α2A subtype mediates hypotension,
sedation and analgesia, as well as inhibition of monoamine
release and metabolism in the brain. The α2B-subtype mediates
vasoconstriction. The α2C-subtype appears to be involved in
feedback inhibition of adrenal cathecolamine release and can
Received: June 19, 2013
Accepted: July 22, 2013
Published: July 22, 2013
© 2013 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
oxidase (MAO).19 On the basis of the interesting results
obtained with 1 and 2, the aim of the present study was to
widen the availability of tools potentially useful in managing
opioid addiction and associated disorders. To this end, we first
determined the 5-HT1A-R profiles of 3 and its enantiomers,8
and 4−6.15 The choice of such compounds was suggested by
the observation that, analogously to 1 and 2, they were
endowed with efficacious α2C-AR agonism/α2A-AR antagonism
due to their preferred extended conformation.15 In addition, the
antidepressant-like effects of 3 and its enantiomers at the low
doses of 0.05 and 0.025 mg/kg, respectively, have been
evaluated in FST. Subsequently, our strategy was directed to
explore another multitarget combination. Therefore, com-
pounds 7−12 were prepared. Such compounds bear the same
Ar region of their corresponding leads 1−6 and the −OCH2−
bridge, which, as mentioned above, is compatible with α2-ARs
and I2−IBS. This compatibility was supported by the results of
our previous studies, which indicated good α2C-AR agonism/
α2A-AR antagonism of 9 (cirazoline) and 1014 and the high I2−
IBS affinity of 7, 9, and 10.20,21 However, the human α2-AR
subtype and 5-HT1A-R profiles as well as the I2−IBS affinities of
7−12 were assessed. For useful comparison, the I2−IBS
affinities of 1−6 were also determined. Finally, the effects of
7, 8, and 10 were evaluated on depression and those of 7 on
acquisition and expression of morphine dependence. The in
vitro and in vivo tests were performed according to previously
reported procedures.8,9,13,22
Chart 1. Chemical Structures of Imidazoline Derivatives
potent antidepressant-like effect. It appeared that the α2C-AR
agonism/α2A-AR antagonism displayed by these compounds
and their enantiomers, represented a suitable condition to
induce positive effects on morphine dependence, while
additional 5-HT1A-receptor (5-HT1A-R) activation, as triggered
by 1 or its (S)-(+) enantiomer and 2 or both its enantiomers,
favored the antidepressant-like effect, recorded in the mouse
forced swimming test (FST).10 Experiments carried out in the
presence of the α2-AR antagonist yohimbine and the 5-HT1A-R
antagonist WAY100135 suggested that dual α2C-AR/5-HT1A-R
activation was required for the antidepressant-like effect
induced by low doses of the aforementioned compounds.9
On the other hand, the participation of 5-HT1A-R in the
antidepressant effect was supported by preclinical results
suggesting that postsynaptic 5-HT1A-Rs are particularly
important in the antidepressant response. Moreover, behavioral
models of stress and antidepressant drug effects in animals,
such as the FST, indicated that the activation of postsynaptic 5-
HT1A-Rs induced changes similar to those of conventional
antidepressants.11
Imidazolines 8, 11, and 12 were prepared according to
Scheme 1. Condensation of the suitable phenols 13−15 with
a
Scheme 1. Preparation of Novel Imidazoline Derivatives
Biologically active ligands bearing the imidazoline nucleus
have been the focus of our studies over the years.12−15 The
present research is a development of our previous observations.
We demonstrated that, in molecular structures sharing the
common pharmacophore reported in Chart 1, the bridge (X)
and the aromatic area (Ar) forming the substituent in position
2 of the imidazoline nucleus displayed different functions.
Indeed, minor chemical modifications of the bridge determined
the preferential recognition of a specific biological system,
whereas those in the Ar region (i.e., introduction of ortho
substituents of different nature) affected ligand affinity and
functional behavior.
In particular, the −OCH(CH3)− bridge, as in 1−6, was
suitable for the α2-AR interaction favored by the recognition of
a lipophilic cavity promoted by the methyl group. In contrast,
this group drastically reduced the I2−imidazoline binding site
(I2−IBS) affinity. Interestingly, the −OCH2− bridge proved to
be compatible with both systems. In the present investigation,
our interest for the I2−IBS was stimulated by the observation
that also these binding proteins are involved in depression and
modulation of morphine analgesia as well as tolerance and
opioid addiction.13,16 The IBS recognize with high affinity
compounds containing the imidazoline moiety. They also
include I1−IBS, which participate in the regulation of
cardiovascular function,17 and I3−IBS, which regulate insulin
secretion.18 Biochemical and pharmacological studies suggest
that the I2−IBS are allosteric sites located on monoamine
a
Reagents and conditions: (a) methyl bromoacetate, K2CO3; (b)
(CH3)3Al, dry toluene, ethylenediamine, Δ.
methyl bromoacetate afforded the esters 16−18, respectively,
which, by treatment with ethylenediamine in the presence of
(CH3)3Al, gave the desired compounds.
The data shown in Table 1 indicate that 3 was endowed with
high 5-HT1A-R affinity (pKi = 8.14) and effective agonism (pD2
= 7.24; %Emax = 92), comparable to those of the known 5-
HT1A-R agonist 8-OH-DPAT.22 These properties were
maintained and even enhanced only by the (S)-(+)-3
enantiomer, whereas (R)-(−)-3 was endowed with negligible
affinity (pKi < 5). Such behavior was analogous to that
observed for 1 and its enantiomers,9 and this similarity was also
confirmed by the FST test.
Indeed, as observed with 1, the same low dose of 0.05 mg/kg
of 3 induced significant reduction of immobility time, and this
effect was comparable to that obtained with the dose of 20 mg/
kg of the selective 5-HT reuptake inhibitor fluoxetine, included
as the reference compound.9 This effect was associated only
with the (S)-(+)-enantiomer, whereas (R)-(−)-3, lacking in
significant 5-HT1A-R affinity, was inactive (Figure 1A). This
observation strengthened the previous result and unequivocally
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ACS Medicinal Chemistry Letters
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a
Table 1. Affinity (pKi), Antagonist Potency (pKb), Agonist Potency (pEC50), and Intrinsic Activity (i.a.) on Human α2-AR
b
c
Subtypes ; Affinity (pKi), Agonist Potency (pD2), and Relative Efficacy (%Emax) on Human 5-HT1A-R ; Affinity (pKi) on I2−IBS
d
on Rat Brain Membranes
α2A
α2B
α2C
5-HT1A
pD2 (pKi)
I2−IBS
pKi
compd
pKb (pKi)
pEC50 (pKi)
i.a.
pEC50 (pKi)
i.a.
%Emax
e
1
7.40 0.06 (7.24 0.11) NA (6.47 0.20)
7.30 0.09 (7.07 0.14) 0.90 6.86 0.09 (7.55 0.16) 67
6.73 0.11 (6.75 0.11) 0.50 (<5)
<6
e
(R)-(−)-1
7.40 0.09 (7.00 0.08) NA (6.25 0.12)
(S)-(+)-1
7.80 0.13 (7.28 0.05) 6.00 0.09 (6.40 0.09) 0.65 7.60 0.14 (7.15 0.09) 0.90 7.19 0.10 (7.45 0.15) 96
7.70 0.12 (7.44 0.09) 5.48 0.15 (6.39 0.05) 0.70 8.70 0.08 (6.56 0.21) 0.80 7.20 0.13 (7.98 0.07) 75
7.20 0.11 (7.35 0.10) 5.40 0.11 (6.47 0.07) 0.65 6.50 0.07 (6.63 0.05) 0.75 6.80 0.10 (7.40 0.08) 68
7.70 0.09 (7.38 0.07) 5.80 0.06 (6.39 0.10) 0.70 8.70 0.11 (6.56 0.13) 0.85 7.40 0.02 (8.24 0.16) 97
2
<6
<6
(R)-(−)-2
(S)-(+)-2
3
7.00 0.09 (7.64 0.20) 5.50 0.15 (6.51 0.13) 0.70 7.40 0.13(7.10 0.16) 0.90 7.24 0.10 (8.14 0.08) 92
e
(R)-(−)-3
6.90 0.07 (7.35 0.10) NA (6.25 0.10)
6.90 0.12 (6.90 0.13) 0.50 (<5)
(S)-(+)-3
7.70 0.11 (7.68 0.12) 5.50 0.13 (6.58 0.08) 0.65 7.45 0.16 (7.20 0.10) 0.90 7.86 0.06 (8.22 0.09) 102
7.05 0.20 (7.30 0.11) 5.30 0.12 (6.27 0.15) 0.60 7.60 0.18 (6.83 0.21) 0.75 7.08 0.11 (7.86 0.05) 118
7.04 0.08 (7.64 0.09) 6.50 0.07 (6.45 0.16) 0.40 8.00 0.11 (6.55 0.09) 0.87 (6.83 0.14)
6.90 0.12 (7.08 0.09) 4.89 0.10 (5.98 0.11) 0.60 7.32 0.13 (6.17 0.14) 0.70 (7.83 0.04)
7.60 0.06 (8.47 0.13) 100
4
<6
<6
<6
5
6
8-OH DPAT
a
b
c
d
The data were expressed as means
SEM of 3−6 separate experiments. According to ref 8. According to ref 22. According to ref 13.
e
Compounds exhibiting i.a. of <0.3 were considered not active (NA).
indicated the crucial role played by the 5-HT1A-R activation in
the observed antidepressant-like effect.
moderate lipophilic character,15 appeared less interesting, 6
proved to be endowed with an important 5-HT1A-R affinity
(pKi = 7.83), probably due to the re-established favorable
combination of the physicochemical parameters of its ortho-
phenyl substituent. Compounds 7−12 (Table 2), devoid of the
methyl group on the bridge, produced α2C-AR agonism, α2A-AR
antagonism, and 5-HT1A-R recognition similar to those of their
corresponding homologues 1−6.
The 5-HT1A-R affinity values at least of 7 and 9 were
unexpected. Indeed, the study of their methyl homologues 1
and 3, which indicated that only the (S) enantiomers interacted
with 5-HT1A-R, suggested that the methyl group on the bridge
played a critical role in the 5-HT1A-R interaction. Moreover, the
5-HT1A-R profile of (R)-(−)-2 compared with those of (R)-
(−)-1 and (R)-(−)-3 and, as mentioned above, the low affinity
of 5 and similarly of 11, demonstrated that this interaction was
also affected by the nature of the ortho-phenyl substituent.
Therefore, modeling studies of the 5-HT1A-R and ligand
docking simulations have been planned. Indeed, they cast upon
possible interactions into the putative 5-HT1A-R binding site
maybe justifying our observations and suggesting useful ortho-
phenyl decorations to enhance the ligand 5-HT1A-R recog-
nition.
Compounds 7 and 9−11 showed interesting I2−IBS
affinities. The I2−IBS pKi values between 8.88 and 7.9 proved
significantly higher than those of the analogues 1 and 3−5 (5 <
pKi < 6). In contrast, reduced and even negligible I2−IBS
affinity was observed for 8 and 12, respectively. Our data
suggest that suitable ortho-phenyl substituents might be
accepted by 5-HT1A and I2−IBS systems. Because of its
interesting in vitro profile, 7 was tested in vivo. From the FST
(Figure 1B), it emerged that 7 induced significant reduction of
immobility time. This effect amounted to 50% at the dose of 5
mg/kg and was comparable to that evoked by 20 mg/kg of
fluoxetine. It increased at higher doses. In contrast to what was
verified for 1−3, no activity was induced at the dose of 0.05
mg/kg. The observation that the anti-immobility effect of 7 was
induced at a dose higher than that requested by 1 and 29 and
that it did not exhibit the dose-dependent U-shaped trend as
shown by both of them suggests that not the 5-HT1A-R
Figure 1. Immobility time in the FST in mice following i.p.
administration of ( )-3 at 0.05 mg/kg, (S)-(+)-3 and (R)-(-)-3 at
0.025 mg/kg (A), and of 7 at 0.05, 1, 5, 10, and 20 mg/kg (B).
Influence of the 5-HT1A-R antagonist WAY 100635 (0.1 mg/kg, s.c.)
and the I2−IBS/α2-AR antagonist idazoxan (2 mg/kg, i.p.) on the
antidepressant-like effect of 7 (5 mg/kg, i.p.) (C). Fluoxetine (FLX; 20
mg/kg) has been included as a reference drug. Data represent mean
( SEM) of 8 animals. Significant differences: **p < 0.01, compared
with vehicle group; °°p < 0.01, compared with antagonist-treated mice;
where not indicated, the differences are not statistically significant.
In addition, the low dose required also for 3 and its (S)-
(+)-enantiomer, both endowed with efficacious dual α2C-AR/5-
HT1A-R agonism, confirmed the already reported peculiar
relationship between α2C-AR activation and 5-HT function.9
From the present study, it also emerged that the racemate 4
displayed high 5-HT1A-R affinity and agonist potency (pKi =
7.86; pD2 = 7.08; %Emax = 118). Therefore, 3 or its (S)-
enantiomer and 4 might, analogously to 1 and 2, represent
novel and advantageous potential tools in managing opioid
addiction and psychiatric comorbidity. Moreover, while 5,
bearing an ortho-phenyl substituent of reduced steric bulk and
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ACS Medicinal Chemistry Letters
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a
Table 2. Affinity (pKi), Antagonist Potency (pKb), Agonist Potency (pEC50), and Intrinsic Activity (i.a.) on Human α2-AR
b
c
d
Subtypes ; Affinity (pKi) on Human 5-HT1A-R ; Affinity (pKi) on I2−IBS on Rat Brain Membranes
α2A
α2B
α2C
5-HT1A
pKi
I2−IBS
pKi
compd
pKb (pKi)
pEC50 (pKi)
i.a.
pEC50 (pKi)
i.a.
7
6.50 0.06 (6.90 0.11)
6.35 0.11 (7.11 0.09)
6.40 0.12 (7.23 0.10)
6.28 0.06 (7.31 0.11)
6.72 0.09 (7.02 0.09)
6.22 0.13 (6.50 0.07)
6.01 0.10 (6.15 0.14)
5.77 0.15 (6.30 0.10)
6.00 0.13 (6.28 0.14)
5.60 0.09 (6.26 0.20)
5.90 0.12 (6.21 0.08)
5.50 0.11 (6.10 0.10)
0.60
0.55
1.0
7.21 0.08 (7.15 0.12)
6.63 0.08 (6.20 0.16)
6.40 0.10 (6.26 0.15)
6.81 0.09 (6.31 0.14)
7.01 0.04 (6.40 0.14)
6.00 0.08 (6.10 0.11)
0.73
0.80
0.80
0.90
0.88
1.0
7.15 0.03
7.08 0.07
7.46 0.16
7.10 0.15
6.25 0.11
7.10 0.09
8.88 0.07
6.90 0.12
8.35 0.11
8.25 0.09
7.90 0.09
<6
8
9
10
11
12
2-BFI
0.70
0.40
0.50
e
e
α2-ARs: (4.57)
8.89
a
b
c
d
e
The data were expressed as means SEM of 3−6 separate experiments. According to ref 8. According to ref 22. According to ref 13. Reference
18.
activation but probably the I2−IBS interaction was involved in
this effect.
This involvement was also justified by the observation that,
while 10 endowed with high I2−IBS affinity (pKi = 8.25)
behaved similarly to 7, 8 displaying smaller affinity (pKi = 6.9),
required the dose of 10 mg/kg for a significant antidepressant-
like effect (Supporting Information, Figures 3 and 4). To
support our observations, 7 was tested in the presence of the 5-
HT1A-R antagonist WAY100135 and the I2−IBS/α2-AR
antagonist idazoxan (Figure 1C). As expected, the pretreatment
with WAY100135 did not affect the antidepressant effect,
which, on the contrary, was significantly contrasted by idazoxan.
This result supported the lack of 5-HT1A-R participation and
confirmed the I2−IBS involvement. The fact that 7 kept the 5-
HT1A-R affinity but not the agonist potency of its methyl
homologue 1 did not contrast with previous results showing
that minor modifications of the chemical structure of 5-HT1A-R
agonists were compatible with the maintenance of the affinity,
but drastically reduced their 5-HT1A-R agonism.23
Figure 2. Effects of acute (A,B) or repeated (C,D) i.p. administration
of 7 (5, 10, 20 mg/kg) on expression and acquisition of morphine
dependence, respectively. Naloxone-precipitated withdrawal symp-
toms, both in control and morphine treated mice, are given as a
measure of the frequency of jumping (A,C) and somatic signs (B,D)
expressed as summary of rearing, forepaw tremors, and teeth chatter.
Data represent mean ( SEM) of 8 animals. Significant differences: *p
< 0.05, **p < 0.01, compared to vehicle; +p < 0.05, ++p < 0.01,
compared to morphine group.
At the dose of 5 mg/kg, 7 was effective both in preventing
acquisition of morphine dependence and countering its
expression (Figure 2).
In particular, on the expression of morphine dependence, the
reduction of the frequencies of naloxone-precipitated jumping
and other somatic signs was >50%. The favorable synergism
induced by effective α2C-AR agonism/α2A-AR antagonism and
I2−IBS interaction might also be underlined by the fact that 2-
BFI, known as a selective I2−IBS ligand (I2−IBS/α2-AR =
2874),18 required higher doses to attenuate morphine with-
drawal24 and to produce an antidepressant effect19 comparable
to that of 7 (10 mg/kg and 19 mg/kg, respectively). However,
higher doses were required by the selective I2−IBS ligands such
as ortho-methylphenyzoline (I2−IBS/α2-AR = 332)13 or
LSL6010125 to attenuate the severity of the withdrawal
syndrome (10 or 20 mg/kg, respectively).
In conclusion, the present study (i) confirms the advantage
of having ligands that display effective α2C-AR agonism/α2A-AR
antagonism/5-HT1A-R agonism. Indeed, 3 or its (S)-enan-
tiomer and 4 might represent novel multifunctional tools
potentially useful in the reduction of withdrawal syndrome and
associated depression at very low dose. (ii) Moreover, it
indicates that also ligands producing significant α2C-AR
agonism/α2A-AR antagonism/I2−IBS interaction, such as 7
and 9−11, might similarly be beneficial to both disorders, as
demonstrated by 7 at the dose of 5 mg/kg. Since I2−IBS are
involved in several psychiatric disorders,16,18 7 and 9−11 might
also relieve further withdrawal comorbid neurobiologic
conditions. Anyway, all the aforementioned multifunctional
compounds, lacking in sedative side effects and potentially
endowed with favorable ADME profiles and limited activity on
the hERG channel, as demonstrated for 1 and 2,8,9 might afford
an improvement over current therapies with clonidine-like
drugs.
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedure, Figures 3 and 4, and elemental analysis of
the final compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*(M.P.) Tel: +39-0737-402257. Fax: +39-0737-637345. E-mail:
maria.pigini@unicam.it.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the MIUR (Rome) and the University of Camerino
for financial support.
■
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ACS Medicinal Chemistry Letters
Letter
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ABBREVIATIONS
■
α2-ARs, α2-adrenoreceptors; 5-HT, 5-hydroxytryptamine; 5-
HT1A-R, 5-HT1A receptor; i.p, intraperitoneally; s.c, subcuta-
neously; I2−IBS, I2−imidazoline binding sites; FST, forced
swimming test; ADME, absorption, distribution, metabolism,
excretion; hERG, human ether-a-
̀
go-go-related gene
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