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Targeting ligand-gated ion channels in neurology and psychiatry: Is pharmacological promiscuity an obstacle or an opportunity?

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The traditional emphasis on developing high specificity pharmaceuticals ("magic bullets") for the treatment of Neurological and Psychiatric disorders is being challenged by emerging pathophysiology concepts that view disease states as abnormal interactions within complex networks of molecular and cellular components. So-called network pharmacology focuses on modifying the behavior of entire systems rather than individual components, a therapeutic strategy that would ideally employ single pharmacological agents capable of interacting with multiple targets ("magic shotguns"). For this approach to be successful, however, a framework for understanding pharmacological "promiscuity"--the ability of individual agents to modulate multiple molecular targets--is needed. Pharmacological promiscuity is more often the rule than the exception for drugs that target the central nervous system (CNS). We hypothesize that promiscuity is an important contributor to clinical efficacy. Modulation patterns of existing therapeutic agents may provide critical templates for future drug discovery in Neurology and Psychiatry. To demonstrate the extent of pharmacological promiscuity and develop a framework for guiding drug screening, we reviewed the ability of 170 therapeutic agents and endogenous molecules to directly modulate neurotransmitter receptors, a class of historically attractive therapeutic targets in Neurology and Psychiatry. The results are summarized in the form of 1) receptor-centric maps that illustrate the degree of promiscuity for GABA-, glycine-, serotonin-, and acetylcholine-gated ion channels, and 2) drug-centric maps that illustrated how characterization of promiscuity can guide drug development. Developing promiscuity maps of approved neuro-pharmaceuticals will provide therapeutic class-based templates against which candidate compounds can be screened. Importantly, compounds previously rejected in traditional screens due to poor specificity could be reconsidered in this framework. Further testing will require high throughput assays to systematically characterize interactions between available CNS-active drugs and surface receptors, both ionotropic and metabotropic.
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HYPOTHESIS Open Access
Targeting ligand-gated ion channels in neurology
and psychiatry: is pharmacological promiscuity an
obstacle or an opportunity?
Matt T Bianchi
1*
, Emmanuel J Botzolakis
2
Abstract
Background: The traditional emphasis on developing high specificity pharmaceuticals ("magic bullets) for the
treatment of Neurological and Psychiatric disorders is being challenged by emerging pathophysiology concepts
that view disease states as abnormal interactions within complex networks of molecular and cellular components.
So-called network pharmacology focuses on modifying the behavior of entire systems rather than individual
components, a therapeutic strategy that would ideally employ single pharmacological agents capable of
interacting with multiple targets ("magic shotguns ). For this approach to be successful, however, a framework for
understanding pharmacological promiscuity - the ability of individual agents to modulate multiple molecular
targets - is needed.
Presentation of the Hypothesis: Pharmacological promiscuity is more often the rule than the exception for drugs
that target the central nervous system (CNS). We hypothesize that promiscuity is an important contributor to
clinical efficacy. Modulation patterns of existing therapeutic agents may provide critical templates for future drug
discovery in Neurology and Psychiatry.
Testing the Hypothesis: To demonstrate the extent of pharmacological promiscuity and develop a framework for
guiding drug screening, we reviewed the ability of 170 therapeutic agents and endogenous mol ecules to directly
modulate neurotransmitter receptors, a class of historically attractive therapeutic targets in Neurology and
Psychiatry. The results are summarized in the form of 1) receptor-centric maps that illustrate the degree of
promiscuity for GABA-, glycine-, serotonin-, and acetylcholine-gated ion channels, and 2) drug-centric maps that
illustrated how characterization of promiscuity can guide drug development.
Implications of the Hypothesis: Developing promiscuity maps of approved neuro-pharmaceuticals will provide
therapeutic class-based templates against which candidate compounds can be screened. Importantly, compounds
previously rejected in traditional screens due to poor specificity could be reconsidered in this framework. Further
testing will require high throughput assays to systematically characterize interactions between availabl e CNS-active
drugs and surface receptors, both ionotropic and metabotropic.
Background
A co mmon assumption und erlying drug discovery is
that therapeutic agents with h igher specificity for their
molecular t argets confer better efficacy and fewer side
effects. Indeed, drug disco very efforts traditionally focus
on developing magic bullets - agents that provide the
proverbial surgical strike against critica l players in a
disease process while minimizing collateral damage.
However, there is growing interest in the possibility that
drug promiscuity (defined as clinically meaningful inter-
action between a drug and m ultiple molecular targets)
may actually represent a therapeutic benefit rather than
a liability. If true, then screening for magic shotguns -
therapeutic agents that are rationally promiscuous -
could be a more effective drug discovery strategy [1-6].
This concept is supported by both theoretical and
empirical studies, and is congruent with our current
understanding of biology in general: that is, genes,
* Correspondence: thebianchi@gmail.com
1
Neurology Department, Sleep Division, Massachusetts General Hospital,
Boston, MA, USA
Bianchi and Botzolakis BMC Pharmacology 2010, 10:3
http://www.biomedcentral.com/1471-2210/10/3
© 2010 Bianchi and Botzolakis; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution Lice nse (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
proteins, and signaling molecules are multi-functional
and comprise a complex network of interactions
[3,4,7-9]. In sight into the effects of therapeutic agents
upon these networks has been fueled by the recent
explosion in genomic and proteomic investigations,
which have elucidated the complex molecular interac-
tions in disease states[9]. Similarly, protein-protein
interaction networks have yielded elaborate datasets
from organisms spanning yeast, nematodes, and
humans, revealing novel sets of potential therapeutic
targets for disease processes [10-12].
Presentation of the Hypothesis
For disorders of the central nervous system ( CNS),
where highly complex interactions underlie normal
function, drug pro miscuity may be parti cularly relevant.
Drug promiscuity is already well-reco gnized among cer-
tain classes of CNS-active modulators such as general
anesthetics [13,14], anticonvulsants [15], and antipsycho-
tics - and this property may extend to other therapeutic
classes such as anti-dementia drugs [16] and even pur-
portedly high-specificity agents such as selective seroto-
nin re-uptake inhibitors (SSRIs) [17,18]. However, it
remains uncertain which subset of promiscuous interac-
tions is important for clinical efficacy. Potential contri-
butors to th is uncertainty include the fruitful history of
linking off-target interactions with side effects, as well as
the e mphasis on high specificity compounds in drug
development. Despite the clear importance of off-target
interactions with side effects, many drugs acting in the
CNS (including some purported to have high specificity)
have been shown to i nteract with multiple targets at
therapeutically relevant concentrations. One approach to
potentially harness promiscuity as a tool for drug dis-
covery is to ascertain which targets are common among
different drugs in a t herapeutic class, thereby e nriching
for the subset of interactions most likely to be therapeu-
tically relevant. We hypothesize that drug discovery stra-
tegies developed to screen for such rational
promiscuity may reveal novel compounds with thera-
peutic efficacy in diseases of the CNS.
Testing the Hypo thesis
To demonstrate that CNS drugs are generally promiscu-
ous agents and illustrate how mapping promiscuity can
guide drug discovery, we collected published examples
of acute, direct funct ional modulation of ligand-gated
ion channels (LGICs) by a total of 170 pharmaceutical
and endogenous molecules, as demonstrated by in vitro
electrophysiology. Although indirect (signal transduc-
tion) and subacute/chronic (plasticity, gene expression)
effects also likely contribute to the clinical efficacy of
many CNS-active drugs, we focused only on direct func-
tional interactions demons trated with physiological
measurements (ion flux and binding data were consid-
ered insufficient). Although the actions of these 170
modulators on the selected LGICs may or may not b e
functionally relevant in vivo , the degr ee of promiscu ity
illustrates the capacity of this c lass of protein targets to
interact with diverse compounds. The potential drug
discovery impact of recognizing clinically relevant pro-
miscuity includes the idea that compound library mole-
cules previously rejected on account of poor specificity
by in vitro screening could be reconsidered in the con-
text of rational promiscuity.
The ligand-gated ion channel family:
evidence for promiscuous modulation
Figure 1 illustrates the promiscuous modulation of four
LGICs (GABA
A
, acetylcholine, glycine, and 5HT-3
receptors) by 170 compounds identified in a systematic
manual se arch of the PubMe d database between 1970
and 2008, as demonstrated by in vit ro electrophysiology
studies. These compounds span categories of psychiatric
medications (Additional File 1: Supplementary Table
S1), anesthetics (Additional File 1: Supplementary Table
S2), anticonvulsants (Additional File 1: Supplementary
Table S3), natural extracts (Additional File 1: Supple-
mentary Table S4), am ino acids and ions (Additio nal
File 1: Supplementary Table S5), steroids (Additional
File 1: Supplemen tary Table S6), endogenous substances
(Additional File 1: Supplementary Table S7), drugs of
abuse (Additional File 1: Supplem entary Table S8), mis-
cellaneous medications (Additional F ile 1: S upplemen-
tary Table S9). The EC
50
,IC
50
, and modulation
percentage are referenced in these tables.
Ofthe170compounds,60%wereactiveatGABA
A
receptors, 56% at nicotinic acetylcholine receptors, 40%
at glycine receptors, and 40% at 5HT-3 receptors. 4 2%
of the compounds interacted with only one LGIC
(located in the four corners of Figure 1), 30% interacted
with two LGICs, 16.5% interacted with three LGICs, and
11% interacted with all four LGICs (located in the cen-
ter of Figure 1). Additional connections may exist, as
not every molecule was tested systematica lly across
these four LGICs. M odulators spanned several cate-
gories, inc luding endogenous species (e.g., amino acids,
ions, steroids) and exogenous molecules (e.g., psychotro-
pic, anticonvulsant, anesthetic, and other FDA-approved
medications). While some of these interactions are
thought to be responsible for clinical efficacy (such as
benzodiazepines potentiating GABA
A
receptors) or side
effects (such as antibiotics ant agonizing GABA
A
recep-
tors), the physiological relevance (if any) of many of
these interactions is unknown. However, the extent of
promiscuity emphasizes the need for systematic charac-
terization if the hypothesis is to be investigated for drug
discovery purposes. Since the evidence for modulation
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was derived from a wide vari ety of sources not explicitly
designed to test for promiscuity, meaningful comparison
of the affinity and efficacy of modulation wa s not possi-
ble (values are neverthele ss shown in Supplemental
Tables, Additional file 1).
It is worth noting that each of these LGICs is actually
comprised of multiple subtypes, each having distinct func-
tional and pharmacological properties. Similar to a recent
pharmacological int eraction network based on databases
of FDA-approved drugs and the ir t argets [19], we have
not presented receptor sub-types, which can have pro-
found influence on modulation. For example, GABA
A
receptors are assembled as heteropentamers from a neu-
ronal repertoire of 19 subunit genes, and subunit compo-
sition is known to influence modulation[20]. The level of
complexity further increases when the promiscuous nat-
ure of the neurotransmitters themselves is considered.
For example, in addition to binding to GABA
A
receptor s,
the neurotransmitter GABA binds to two additional
receptor classes (metabotropic GABA
B
and ionotropic
GABA
C
receptors), as well as to a subset of glycine recep-
tors in vivo [21,22]. In fact, the ability of classical neuro-
transmitters to interact directly with non-canonical
targets is well- recognized: glycine is a co-agonist for
NMDA-type glutamate receptors, serotonin can activate
nicotinic acetylcholine receptors, and dopamine is an ago-
nist at serotonin re ceptors. Mo reover, experimental mea-
surements o f modulation are themselves influenced by
receptor properties s uch a s agonist affinity, efficacy, and
desensitization [23,24]. Modulation mechanisms can be
influenced by the modulator concentration: neurosteroids
and barbiturates allosterically modulate GABA
A
receptors
at low concentrations, act as direct agonists as higher
concentrations, and open channel blockers at even higher
concentrations concentrations [25-27]. Direct receptor-
receptor interac tions, independent of second messenger
systems, also contributes to complexity [28-31]. Local
drug concentration profiles may also exhibit complex reg-
ulation within and outside synapses, or via lipid rafts that
alter their effective concentration [32].
Figure 1 Promiscuous modulation of ligand-gated ion channels. The four members of the cys-loop family of ligand gated ion channels are
shown as black nodes. Endogenous and exogenous modulators exhibiting electrophysiologically confirmed modulation of one or more of these
channel classes are indicated by a blue line connecting the modulator to the receptor(s). Modulators in the four corners are those showing
documented modulation of only one channel class, while those centrally located modulate all four classes. Endog, endogenous; AA, amion acids;
misc, miscellaneous; anesth, anesthetics; AED, anti-epileptic drug; psych, psychiatric. This figure was generated using Cytoscape software.
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Drug-centric promiscuity maps
Drug promiscuity can also be evaluated from the reverse
perspective, focusing i nstead on the ability of a single
therapeutic agent to interact with multiple protein tar-
gets. The most comprehensive approach, illustrated in
Figure 2A using t he example of SSRIs, is to include
both d irect and indirect ta rgets. Although cl assically
thought to be highly selective agents, three points are
immediately apparent from the SSRI map. First, promis-
cuity exists a t the level of direct interactions of SSRIs
with CNS targets [17] . Second, one of th e direct targets,
the rate-limiting step in neurosteroid biosynthesis, leads
to the production of additional promiscuous modulators,
each of which affects various downstream targets.
Finally, the SSRI-induced increase in serotonin concen-
tration potentially impacts numerous serotonin receptor
Figure 2 Promiscuity maps. A. SSRIs interact with multiple classes of ion channels, and increases neurosteroid synthesis (by directly modulating
a rate limiting enzyme activity), in addition to its activity on the serotonin reuptake transporter (SERT). Neurosteroids are themselves promiscuous
modulators of ion channels, and some of these interactions are shown (dotted lines from purple box). The impact of increasing serotonin is
manifest at potentially any of seven categories of serotonin receptor (each with several subtypes), spanning ionotropic, metabotropic, varying
localization, and different second messenger cascades. B. Promiscuity map of direct interactions of SSRIs with various metabotropic receptors and
transporters (polygons), as well as ion channels (rectangles) including K channels (blue), Ca channels (green), LGICs (yellow). Distance from the
central SSRI node approximates the log-scaled affinity of SSRI for the various targets. Concentric dotted circles reflect 3 orders of concentration
magnitude (0.1, 1, and 10 μM). Therapeutic SSRI concentration in vivo is between 1-10 μM, that is, between the middle and outer circle. This
figure was generated using CellDesigner software.
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subtypes, spanning multiple signaling processes (pre-
and post-synaptic, excitatory and inhibitory, ionotropic
and metabotropic, and different second messenger
systems).
For drug screening purposes, however, mapping only
direct interactions may be more explicitly useful. An
example is shown in Figure 2B, where the direct modu-
lation of multiple targets by SSRIs is illustrated. The
EC
50
or IC
50
of SSRIs for each target is approximated
by the radial distance from the center of the map (based
on electr ophysiology dat a for the ion channel tar gets
and on binding data for the metabotropic target recep-
tors). The radius of the outer two concentric circles
spans the range of estimated the rapeutic CNS concen-
tration (1-10 μM) [17]. With this approach, the extent
of drug pro miscuity can easi ly be visualized in reference
to therapeu tically relevant concentrations. Of note,
while the affinity of SSRIs for the primary target, the
serotonin transporter, is ~50 nM, the therapeutic CNS
concentration range in humans is estimated to be more
than 10-fold higher, r aising the possibility of clinically
important interactions with numerous other t argets. It
should also be emphasized that affinity doe s not entirely
capture the potential for significant interaction. For
example, although the EC
50
for fluoxetine enhancement
of GABA
A
receptors was 128 μM, the enhancement was
large (350%), suggesting mod ulation could occur at con-
centrationsaslowas10μM[33].Furthermore,the
major metabolite norfluoxetine was over 100× more
potent in the same study (EC
50
0.7 μM).
Using promiscuity mapping to guide drug discovery
Using promiscuity maps to guide drug discovery cou ld
proceed as follows. First, a drug-centric promiscuity
map akin to that shown in Figure 2B w ould be gener-
ated for each drug in a therapeutic class, possibly group-
ing drugs with similar clinical efficacy (Figure 3). Then,
targets shared by all members of the class would be
identified, thus representing the subset of interactions
presumably linked t o the desired clinical effect. Non-
shared targets would also be identified, as these are pre -
sumably less ther apeutically relevant and/or responsible
Figure 3 A rational promiscuity approach to drug screening. Coverage maps a re generated for individual drugs, here plotted a s relative
affinity for targets A-J indicated by radial distance from the origin (in arbitrary units). Combining the maps clearly illustrates that targets A-F are
shared by all 3 drugs (dotted line). Subsequent screening algorithms would enrich for targets A-F, while avoiding non-shared targets G-J.
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for drug-specific side effects. Screening (or design) of
rationally promiscuous drugs would then aim to
reproduce the shared interactions across similarly effica-
cious compounds, while avoiding non-shared targets
(Figure 3). Granted, this strategy may be somewhat
oversimplified sinc e side effects could be shared and
thus selected for in such a prom iscuity analysis. Addi-
tionally, it is conceivable that targets not shar ed by all
members of a class could be relevant for individual
patient differences in efficacy seen clinically. Howeve r,
these are both potentially testable hypotheses through
systematic analysis of promiscuity, followed by rational
design of drugs exhibiting distinct coverage maps. The
currently sparse experimental coverage of possible inter-
actions precludes even preliminary estimates of sha red
targets. Advances in high throughput electrophysiology
will facilitate implementation of this screening strategy.
Implications of the Hypothesis
The in vivo cellular and molecular milieu involves com-
plex interactions between cellular and molecular compo-
nent s. However, because these components are typically
studied experimentally in is olation, it remains largely
uncertain how such complexity influences signaling dur-
ing normal brain funct ion or disease states. Moreover,
few studies have endeavored to explore the effect of
simultaneous endogenous and pharmacological modula-
tors acting on a receptor target, mainly because of the
cumbersome combinatorial nature of studying even a
subset of the possible interactions. Given the evidence
for promiscuity of endogenous as well as therapeutic
modulators of neurotransmitter receptors highlighted
here, we propose that such information may be biologi-
cally and clinically relevant.Indeed,byaimingvarious
high throughput functional assays toward the systematic
elucidation of promiscuity maps, we anticipate that new
vistas of drug disco very will be revealed. One imp ortant
implication of this strategy is that one can re-investigate
existing compounds that have been discarded in early
preclinical studies solely on the basis of failing high spe-
cificity criteria.
The magic shotgun approach to complex disease
processes
Three lines of reasoning argue against the assump-
tion that higher specificity drugs will necessarily confer
increased therapeutic efficacy. First, endogenous
receptors and signaling molecules are themselves
multi-functional, exhibiting b oth ligand-centric and
receptor-centric p romiscuity. Thus, even theoretically
high specificity agents could have unpredictable biologi-
cal impact, if the intended target were involved in many
functions. Second, target promiscuity may be more com-
mon than recognized for many CNS-active therapeutics
[14,15,17,18], raising the possibility that promiscuity in
fact contributes to the clinical efficacy. Finally, there is
growi ng evidence that complex networks are more opti-
mally modulated by mult i-target appr oaches [8], su g-
gesting a paradigm shift from the dominant magic
bullet strategy to what has become known as the
magic sho tgun approach to therapy[3,4,7,34]. Indeed,
to treat most CNS disorders, drugs must limit patholo-
gical neur onal activ ity without disrupting the rich
underlying functionality of the brain. The existing e vi-
dence for promiscuity raises the possibility that m odu-
lating multiple nodes of a ne twork of i nteracting
components may be more appro priate for the complex
pathophysiology of CNS diseases. An intriguing specula-
tion is that highly s pecific drugs could invoke greater
compensatory homeostatic processes, which may relate
to tolerance and/or to side effects. Is it possible that a
multi-pronged modulati on strat egy, with ea ch prong
perhaps providing a relatively small effect (that evades
large homeostatic cellular responses), would not only be
more efficacious, but potentially also reduce side effects?
Recent advances in imaging large networks of neuronal
firing may shed light on the network-level impact of
drugs thought to interact with multiple targets in clini-
cally relevant situations such as depression models [35].
Promiscuity and clinical efficacy of CNS-active drugs
Rational approaches to promiscuity may inform poten-
tial drug discovery strategies that c onsider the patterns
of target modulation in relation to pharmaceutical effi-
cacy as well as side effects. Endogenous signal transduc-
tion pathways, such as G-protein coupled receptors and
receptor kinases, likely also demonstrate modulator pro-
miscuity, and should be considered in addition to ion
channel targets. Several models have been proposed to
address the potential molecular basis of target-receptor
promiscuity based on atomic-level interactions [36], as
well as the propensity for promiscuous versus specific
protein-protein interactions in crowded cellular envir-
onments [37]. Other analysis, arguing in favor of the
importance of specificity, suggested that promiscuity
was more commonly evident in drugs that did not reach
the clinic[38], perhap s due to side effects. Finally, a
recent repor t used ligand-recep tor interaction models to
explore previously unknown off-target interactions
experimentally [5].
The f undamental challenge of m odern CNS pharma-
cology is to determine which aspects of drug promiscu-
ity contribute to clinical efficacy, and which aspects are
responsible for unwanted side effects[39]. To gain novel
insight into normal and pathological physiology as well
as potential therapeutic interventions, a multidisciplinary
effort is required that combines high throughput techni-
ques and informatics approaches. Rational exploration
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of the promiscuity parameter space represents one strat-
egy for improvi ng drug d iscovery by usi ng existing drug
classes as a template for future rational design.
Additional file 1: Tables of modulator-target interactions.EC
50
,IC
50
,
percent modulation, and references for each modulator-target
interaction.
Click here for file
[ http://www.biomedcentral.com/content/supplementary/1471-2210-10-3-
S1.DOC ]
Acknowledgements
The authors thank Drs. Sydney Cash and Verne Caviness for valuable
comments and discussion. MTB receives funding from the Department of
Neurology, Massachusetts General Hospital, and the Clinical Investigator
Training Program: Harvard/MIT Health Sciences and Technology - Beth Israel
Deaconess Medical Center, in collaboration with Pfizer, Inc. and Merck & Co;
EJB receives funding from NIH T32-GM07347 to the Vanderbilt Medical
Scientist Training Program (MSTP).
Author details
1
Neurology Department, Sleep Division, Massachusetts General Hospital,
Boston, MA, USA.
2
Medical Scientist Training Program, Vanderbilt University
School of Medicine, Nashville, TN, USA.
Authors contributions
MTB and EJB contributed equally to conceiving the study and its design,
interpretation, figure development, and drafting of the manuscript. MTB
carried out the primary literature analysis. Both authors read and approved
the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 13 October 2009
Accepted: 2 March 2010 Published: 2 March 2010
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Cite this article as: Bianchi and Botzolakis: Targeting ligand-gated ion
channels in neurology and psychiatry: is pharmacological promiscuit y
an obstacle or an opportunity?. BMC Pharmacology 2010 10:3.
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Supplementary resource (1)

... The fusion of network science and drug research was first conceptualized by Andrew L. Hopkins based on the premise of poly-pharmacology-one drug, multiple targets [24]. This holistic view has been appreciated in psychiatry, in which many psychotropic drugs have been shown to exhibit promiscuity as an intrinsic feature of their therapeutic effects [25]. Antipsychotics are prominent examples. ...
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... Ionotropic receptors have a variety of triggering mechanisms, including ligand-gated, mechanosensitive, and chemosensitive. The ligand-gated ionotropic channels are highly expressed in a wide variety of tissues and have been successfully targeted to modulate their function since the 1950s (Bianchi and Botzolakis, 2010). ...
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