NOpiates: Novel dual action neuronal nitric oxide synthase inhibitors with μ-opioid agonist activity

Article abstract of DOI:10.1021/ml200268w

A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the μ-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the μ-opioid GPCR was predicated on the modulatory role of nitric oxide on μ-opioid receptor function. Structure-activity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC₅₀ = 0.44 μM), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent μ-opioid binding affinity, K_i = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC₅₀ = 0.34 μM). This work represents a novel approach in the development of new analgesics for the treatment of pain.

Full text of DOI:10.1021/ml200268w

Letter
pubs.acs.org/acsmedchemlett
NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase
Inhibitors with μ-Opioid Agonist Activity
Paul Renton,* Brenda Green,† Shawn Maddaford, Suman Rakhit, and John S. Andrews
NeurAxon Inc., 2395 Speakman Drive, Suite #1001, Mississauga, Ontario, L5K 1B3, Canada
S
* Supporting Information
ABSTRACT: A novel series of benzimidazole designed multiple ligands (DMLs)
with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the μ-
opioid receptor was developed. Targeting of the structurally dissimilar heme-
containing enzyme and the μ-opioid GPCR was predicated on the modulatory role
of nitric oxide on μ-opioid receptor function. Structure−activity relationship
studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC50
=
0.44 μM), selectivity over both endothelial nitric oxide synthase (10-fold) and
inducible nitric oxide synthase (125-fold), and potent μ-opioid binding affinity, Ki
= 5.4 nM. The functional activity as measured in the cyclic adenosine
monosphospate secondary messenger assay resulted in full agonist activity (EC50
= 0.34 μM). This work represents a novel approach in the development of new
analgesics for the treatment of pain.
KEYWORDS: nitric oxide, opioid, dual action, benzimidazole, NOS inhibitor, NOpiate, NOpioid
pioid analgesics are one of the most important classes of
drugs and represent the cornerstone of pain manage-
ligand (DML)14 paradigm with the specific aim of incorporat-
ing μ-opioid agonism and nitric oxide synthase (NOS)
inhibition into a single new chemical entity (NCE).
O
ment. Although opiates have a long history of successful
management of pain, there is a continued interest in the
development of new opioid analgesics to overcome their
numerous liabilities that include respiratory depression, nausea,
sedation, constipation, dependency, abuse, and the develop-
ment of tolerance.1,2 In the case of chronic and neuropathic
pain, opiate use fails to adequately address the features of
hyperalgesia and allodynia, yielding suboptimal pain relief in
many patients.3−5 Paradoxically, chronic administration of
opiates may be self-limiting as a result of the development of
opioid-induced hyperalgesia (OIH),6 an enhancement of the
pain response attributed to adaptative changes in the central
nervous system such as upregulation of the cyclic adenosine
monosphospate (cAMP) pathway and increased production of
nitric oxide (NO).
It has been suggested that compounds acting upon multiple
mechanisms of action could better address the shortcomings of
current pain therapies by enhancing efficacy and reducing side
effects.3,7,8 The importance of multiple mechanisms acting in
concert either additively or synergistically to treat pain has been
exemplified by the polypharmacology of opioid combinations
such as oxycodone-acetominaphen, morphine-oxycodone,
morphine-δ antagonists, and morphine-gabapentin.9−11 How-
ever, the development of combination drugs is complicated by a
need to optimally match pharmacokinetic properties and by
difficulties in predicting drug interactions, dissolution rates, and
stability in the formulated product.12
NO is synthesized by three highly related isoforms (neuronal
or nNOS, endothelial or eNOS, and inducible or iNOS) and
regulates neurotransmission, blood pressure, and inflammatory
responses, respectively.15 NO is known to play an important
role mediating nociceptive processing in sensitized pain
states,16 and NOS inhibitors are effective in animal models of
neuropathic and inflammatory pain.16−19 In addition, non-
selective NOS inhibitors L-nitro arginine methyl ester (L-
NAME) and 7-nitroindazole (7-NI) potentiate opioid analgesia
in pain models and reduce morphine tolerance. However, this
effect is lost in nNOS knockout mice, suggesting that the
neuronal form is important in modulating opioid analgesia and
tolerance.20,21
With this in mind, while recognizing the difficulty inherent in
integrating the pharmacophoric elements from two highly
dissimilar targets14,22 (nNOS, a heme-containing enzyme, and
the μ-opioid GPCR), we initiated a program to develop a dual-
acting selective nNOS inhibitor (i.e., lacking eNOS and iNOS
inhibition) with μ-opioid agonist activity. Common structural
features between etonitazene,23 a potent μ-agonist (Ki = 0.2
nM), and previously published nNOS inhibitors were
envisioned (Figure 1).24,25
Both the central aryl scaffold and the basic amine side chain
were apparent in the etonitazene framework. Determination as
to whether incorporation of a guanidine isostere [which makes
In our approach to address the pressing need for the
development of improved analgesics targeting novel pain
pathways,3,13 we adopted the dual action or designed multiple
Received: November 10, 2011
Accepted: January 19, 2012
Published: January 30, 2012
© 2012 American Chemical Society
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Letter
group ortho to the secondary amine was achieved by a Zinin
reduction.29 Subsequent separation from the para diamino
regioisomer exploiting dry column chromatography techniques
yielded the 1,2-diaminobenzenes 6−9. Condensation with 2-(4-
ethoxyphenyl)acetic acid in the presence of 2-ethoxy-1-
ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) followed by
PCl5-induced cyclization30 yielded the key benzimidazole
intermediates 14−17. Reduction of the nitro group to the
corresponding amino group under atmospheric hydrogenation
conditions and subsequent reaction in situ with one of methyl
thiophene-2-carbimidothioate·hydroiodide (HI) (18), benzyl
furan-2-carbimidothioate·hydrobromide (HBr) (19), benzyl
thiophene-3-carbimidothioate·HBr (20), benzyl furan-3-carbi-
midothioate·HBr (21), naphthalen-2-ylmethyl ethanimido-
thioate·HBr (22), or 1-methyl-3-nitro-1-nitrosoguanidine (23)
yielded final compounds 24−32.31 Utilizing the reduction/
amidine formation sequence (vide supra), the six-substituted
regioisomer of 24 was synthesized from known compound
33,25 as shown in Scheme 2. All compounds were converted
into their corresponding dihydrochloride salts.
Figure 1. Proposed dual action structure.
an important bidentate interaction with the conserved glutamic
acid residue at the arginine (substrate) binding site of the NOS
enzyme] would be tolerated without significant loss of μ-opioid
binding ability was paramount. Although little has been
published on the binding interactions of etonitazene,26 two
literature reports suggested that upon replacement of the nitro
group, antinociceptive activity could be retained albeit weaker
than etonitazine itself.27,28 Herein, we report the synthesis of a
series of dual action substituted benzimidazoles with selective
inhibitory activity toward the human nNOS isoform and
activity at the μ-opioid receptor.
The inhibitory activities of the target compounds against
human NOS isoforms,32 their binding affinity to the human μ
opioid receptor,33 and a functional measurement of agonist-like
activity (the ability to inhibit forskolin mediated cAMP
production)33 were assessed (Table 1).
Compound 24 was identified as the most potent nNOS
inhibitor [IC50 = 0.44 μM, more potent than the clinically
active nonselective NOS inhibitor (L-NMMA)], while
Preparation of the 1,2,5-trisubstituted benzimidazole ana-
logues was achieved as outlined in Scheme 1 utilizing a
modified version of the original synthesis of etonitazene.23
The tertiary amino side chains were introduced via
nucleophilic aromatic substitution of the chloro group of 1-
chloro-2,4-dinitrobenzene 1 with various diamines. Recrystal-
lization from EtOH yielded the 2,4-dinitro-substituted anilines
2−5. Preferential reduction (commonly >5:1) of the nitro
a
Scheme 1. Synthesis of Trisubstituted Benzimidazole Final Compounds 24−32
a
Reagents and conditions: (a) Various diamines (H2NR), EtOH, reflux. (b) Aqueous (NH4)2S, EtOH, H2O, 70 °C. (c) 2-(4-Ethoxyphenyl)acetic
acid, EEDQ, CH2Cl2 or THF, 35−60 °C. (d) PCl5, CHCl3, reflux. (e) Pd−C/H2, EtOH, room temperature. (f) Methyl thiophene-2-
carbimidothioate·HI (18) or benzyl furan-2-carbimidothioate·HBr (19), EtOH, room temperature. (g) Benzyl thiophene-3-carbimidothioate·HBr
(20) or benzyl furan-3-carbimidothioate·HBr (21), EtOH, room temperature. (h) Naphthalen-2-ylmethyl ethanimidothioate·HBr (22), EtOH, room
temperature. (i) 1-Methyl-3-nitro-1-nitrosoguanidine (23), EtOH, reflux.
228
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ACS Medicinal Chemistry Letters
Letter
a
Compounds 24, 25, 28, 29, and 30 were selective (5−23-
fold) for the nNOS over the eNOS isoform. To obtain
compounds devoid of the cardiovascular liabilities associated
with eNOS inhibition,34 selective nNOS inhibition is required.
In this series of compounds, the acyclic basic amine side chains
showed improved nNOS/eNOS selectivity in comparison to
the cyclic amino side chain 27. Thiophene amidines 24 and 29
were more potent for the nNOS and eNOS isoforms when
compared to the corresponding furanyl amidines 28 and 30,
respectively. Suprisingly, compounds 31 and 32 show weak
inhibitory activity at NOS despite the presence of the
acetamidine (31) and nitroguanidine (32) moieties, two
functional motifs that have been utilized successfully in
previous NOS inhibitors.35 However, 32 displayed excellent
activity in the μ-opioid functional assay (52 nM), suggesting an
important interaction of the nitro group of etonitazene and
potentially 32 that facilitates potent functional activity. In
Scheme 2. 6-Regioisomer of Compound 24
a
Reagents and conditions: (a) Pd−C/H2, EtOH, room temperature.
(b) Methyl thiophene-2-carbimidothioate·HI (18), EtOH, room
temperature.
demonstrating selectivity over eNOS (10-fold preference for
nNOS); iNOS (125-fold) and importantly showed potent
binding affinity (Ki = 5.4 nM, comparable to morphine) at the
μ-opioid receptor in a competitive radioligand binding assay.
a
Table 1. Inhibition of Human NOS Enzymes and MOP Binding and Functional Data
a
b
c
Values reported in parentheses are 95% confidence intervals. NT, not tested. >100, not active at the maximum test concentration of 100 μM.
Data from ref 38.
d
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contrast to the 5-substituted analogue 24 and other 1,6-
substituted bicyclic scaffolds,36 the six-substituted regioisomer
34 shows much weaker nNOS inhibition (85-fold).
synthase; L-NAME, L-nitro arginine methyl ester; NCE, new
chemical entity; 7-NI, 7-nitroindazole; NO, nitric oxide; NOS,
nitric oxide synthase; nNOS, neuronal nitric oxide synthase;
OIH, opioid-induced hyperalgesia
Select compounds showed nanomolar level potency in the
opioid binding assay but with reduced functional activity.
However, these compounds displayed full agonist properties at
the μ-opioid receptor. Because of the potential synergies of the
dual mechanisms, the functional activity may not need to be as
potent as morphine. For example, both Tramadol (and its more
active desmethyl metabolite; see Table 1) and Tapentadol (30-
fold weaker than morphine in a [35S]GTPγS functional assay)
are clinically utilized centrally acting analgesics despite showing
modest functional activity at the μ-opioid receptor, likely due to
the synergy of nonopioid mechanisms (primarily monoamine
reuptake inhibition).37,38
In conclusion, we have designed and synthesized a series of
novel dual action nNOS inhibitors with μ-opioid agonist
activity and selectivity for nNOS over eNOS. This is the first
report of a DML combining μ-opioid activity and selective
nNOS inhibitory activity. It is notable that this represents one
of the few cases of the successful design for two structurally
distinct macromolecular targets (GPCR and oxygenase
enzyme) as the majority of reported DMLs target similar
subclasses.14,22 The lead compound 24 inhibited nNOS more
potently than L-NMMA and displayed a level of potency
similar to morphine in a μ-opioid binding assay. Thus, having
achieved proof of concept of dual targeting of these dissimilar
pain targets, future efforts will be focused on evaluating the
potential synergistic effects of combined nNOS/μ-opioid
mechanisms in animal models of acute and chronic pain.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures, analytical characterization and purity
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This material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
*Tel: 1-416-673-6697. E-mail: prenton@neuraxon.com.
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Present Address
†Institute of Biomaterials and Biomedical Engineering,
University of Toronto, Toronto, ON, M5G 1L7, Canada.
Funding
We thank the Natural Sciences and Engineering Research
Council (NSERC) of Canada for providing an undergraduate
student research award (USRA) to B.G.
Notes
The authors declare no competing financial interest.
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ABBREVIATIONS
■
cAMP, cyclic adenosine monosphospate; DML, designed
multiple ligand; EEDQ, 2-ethoxy-1-ethoxycarbonyl-1,2-dihy-
droquinoline; eNOS, endothelial nitric oxide synthase; HBr,
hydrobromide; HI, hydroiodide; iNOS, inducible nitric oxide
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