Selective Targeting of the Nicotinic Alpha7 Receptor

Selective Targeting of the Alpha7 Nicotinic Receptor for Treating Neuropathic Pain
Nikil H. Patel
Capstone Project Summer 2014
Northeastern University
Advising Professor: Dr. G.A.Thakur

Selective Targeting of the Nicotinic Alpha7 Receptor for Treating Neuropathic Pain [N. H. Patel]
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Abstract:
Neuropathic pain is a chronic, complex regional pain state that usually involves
dysfunction, injury or damage to nerve fiber tissue making it a difficult condition to treat. Of the
medications currently available for treating neuropathic pain to today, majority lack the desired
potency or are accompanied by adverse effects thus are limited in medical use. Over the past
decade, several classes of medications have been developed to target a specific group of nicotinic
acetylcholine receptor subunits and have shown to be beneficial in treating chronic pain
disorders. This paper reviews a number of these developed compounds and classes of
medications and explores the functional role of the α7 nAChR subunit for the treatment of
neuropathic pain.
Article History:
Started: June 2014
Submitted: August 2014
Keywords:
nAchRs, α7, Pain, Neuropathic Pain, Chronic Pain, Inflammation, Analgesia, Antinociception, Positive Allosteric
Modulators, Allosteric Agonists, Silent Agonists
Abbreviations:
ACh – Acetylcholine
nAChR – Nicotinic Acetylcholine Receptors
α7 – Alpha 7 receptor of the nAChR class
PAM – Positive Allosteric Modulators
Ago-PAM – Allosteric Agonist- Positive Allosteric Modulators
CNS – Central Nervous System
Table of Contents:
Introduction ……………………………………………………………………...... pg. 3
Nicotine and Analgesia ……………………………………………………………….... pg. 4
Neuropathic Pain ………………………………………………………………………. pg. 4
Research Methods…………………………………………………………………. pg. 6
Discussion ………………………………………………………………………… pg. 7
α7 Agonists …………………………………………………………………………… ..pg. 8
PAMs [ I, II, and Intermediate] ……………………………………………………….. pg. 10
Ago-PAMS ……………………………………………………………………………. pg. 12
Conclusion ……………………………………………………………………..…. pg. 13
Acknowledgements ……………………………………………………………...... pg. 14
References ………………………………………………………………………… pg. 15

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1. Introduction
Nicotinic acetylcholine receptors (nAChRs), commonly referred to as inotropic
acetylcholine (ACh) receptors, are a type of receptor protein involved in the physiological
response to ACh, and have a strong affinity for nicotine. These cholinergic receptors are
structurally comprised of five subunits (known human subunits: α2- α10 ; β2-β4) which form
ligand-gated ion channels, allowing the
passage of cations such as calcium,
potassium and sodium through the
plasma membranes of certain neurons.
nAChRs can be structurally made from
either homomeric α subunits or through
a heteromeric α/β subunit combination [Gotti C. et al., 2006]. In recent years, studies have shown that
these receptors are expressed in abundance throughout the central and peripheral nervous system
which has sparked interest in their use to treat several medical disorders [Gotti C. et al., 2006].
Of these receptors, one in particular stands apart due to its characterizing features. The α7
nAChR is a homomeric subtype that has been identified to have a higher calcium permeability,
shorter activation rate and undergoes desensitization (during agonist stimulation) faster in
comparison with the other nAChR subtypes [Feuerbach D. et al., 2009]. It is these key features coupled
with nAChR α7’s physical locations within the body that has led researchers to believe that these
receptor sites could be a promising target for treating a wide range of medical disorders some of
which include cognitive impairments, smoking cessation, thermoregulation, inflammation and
neuropathic pain.
Figure 1: Representative ligand-gated ion channel

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1.1 Nicotine and Analgesia
Although targeting nAChRs to relieve pain is a relatively new concept, the association
between nicotine and analgesia has been well known [Hamann S. & Martin W., 1992]. In the early 16th
century, Spanish historian Oviedo Valdes first associated the reduction in pain with smoking
tobacco (nicotine being the main constituent) [Umana I. et al., 2013]. Over the years we have learned the
extent of tobacco and nicotine’s adverse effects which has limited them to be viewed as
ineffective agents for treatment [Hamann S. & Martin W., 1992]. It was not until 1974, when John Daly and
Charles Myers discovered that the skin secretions of a frog found in Ecuador produced opioid
like effects in a rodent pain study [Daly et al., 2000]. The active chemical within the secretions was
later found to be epibatidine, a nonselective nAChR agonist [Daly et al., 2000]. During animal testing,
it was observed that epibatidine produced an antinociceptive efficacy comparable to morphine
with 100-fold higher potency when using the hot plate test [Daly et al., 2000]. However, similar to
nicotine, epibatidine also showed to induce sensitization and adverse effects (decrease in body
temperature and locomotor activity) [Daly et al., 2000]. Though this did indicate the possibility that due
to the non-selective nature of epibatidine, some subsets of nAChRs may facilitate antinociceptive
properties while others potentiate adverse effects.
1.2 Neuropathic Pain Today
One area in which targeting nAChRs may prove to have a significant use is in the
treatment of neuropathic pain. nAChRs have been found expressed throughout the CNS,
including several areas where pain signaling is modulated: the medulla, midbrain, nucleus raphe
magnus, thalamus and spinal cord [Scadding J., 2003]. This discovery, along with the pharmacological
effects of epibatidine, is what has lead researchers to question whether there is a correlation
between the nAChRs and nociceptive effects. Neuropathic pain is a chronic, complex regional

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pain state that usually involves dysfunction, injury or damage to nerve fiber tissue [D’Arcy Y., 2014].
Unlike acute pain, neuropathic pain can persist even if all signs of a lesion have dissipated, as
well as in the absence of a stimulus (nociceptive input) [Irving G., 2005]. This condition is most
commonly caused by a disorder/ irregularity of the peripheral or central nervous system and can
affect a wide array of receptors involved in the somatosensory system [D’Arcy Y., 2014]. Some
common disease states in which neuropathic pain is often reported include arthritis, multiple
sclerosis, stroke, diabetes, HIV, B12 deficiency, malignancy and syphilis [D’Arcy Y., 2014; Scadding J.,
2003].
Current pharmacological therapy options in treating chronic pain states include non-
steroidal anti-inflammatory drugs (NSAIDs), tricyclic anti-depressants, anticonvulsants, topical
anesthetics and opioids. The dilemma in treating chronic pain with several of these products
encompasses either a limited efficacy, as is the case with the NSAID products, or the
development of sensitization and tolerance which are characteristics of opioid medications that
often leads to their abuse [Scadding J., 2003]. Opioids in particular over the past couple decades have
seen an increase in prescriptions written for the treatment of chronic, non-cancer related, pain
[Hamann S. & Martin W., 1992; Umana I. et al., 2013]. During the same period, the Journal for Drug and Alcohol
Dependence noticed that there was a positive correlation between the number of opioid pain
prescriptions dispensed and the number of opioid abuse cases reported [Umana I. et al., 2013]. Thus, due
to this growing trend it is imperative that we start looking to new compounds which can help
combat neuropathic pain, and the α7 nAChR may be just the place to start looking.

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2. Research Methods
For this article a considerable amount of research was conducted to obtain all relevant
information pertaining to this topic. The gathered information required for this article was
generated through the use of
various medical subject
headings (MeSH terms) or
keywords searched as seen.
The following table is a
notation of the keywords
used as well as the number of
publications associated with
each term, as on nlm.nih.gov.
The articles used within the
discussion have either been
approved by the National Institute of Health, American Chemical Society or the leading
researchers from the Virginia Commonwealth University Department of Pharmacology and
Toxicity.
It was observed that although a significant amount of research has already been
conducted regarding the nAChRs, very few articles (in relation) have delved into their potential
use as analgesic targets. The majority of the data up to date revolves around their potential uses
for pro-cognitive treatment in schizophrenia and Alzheimer’s disease, inflammatory disorders
and as smoking cessation agents. In addition to this, of the nAChR studies that have been
published, the majority have focused on the heteromeric α4β2 subtype due to it being the most
Key words Sub Searches # of listed citations
Neuropathic Pain 30889
Pain, Nicotinic 773
nAChR 156
alpha7 86
α7 86
Nicotinic Acetylcholine Receptor, 19397
Agonist 4769
Modulators 295
nAChR, 4389
Agonist 1063
Modulator 106
Alpha7 (α7), 3717
Agonist 866
Antagonist 784
Modulator 117
Alpha7 (α7) activation, 886
Human trials 11
Animal trials 8
Table 1: nlm.nih.gov //PubMed Searches
Selective Targeting of the Nicotinic Alpha7 Receptor’s use in Treating Neuropathic Pain

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widely distributed nAChR within the CNS [Hurst R. et al., 2013]. Although recent studies have shown
that despite the accumulating evidence showing highly selective α4β2 agonist’s (ABT-894)
effect in reducing pain in animal models [Umana I. et al., 2013], human trial data suggests that the
therapeutic window between antinociceptive effects and toxicity is too narrow [Rowbotham M. et al.,
2012].
3. Discussion
Since John Daly and Charles Myers’ discovery of epibatidine, several ligands targeting
the nAChRs have been synthesized and evaluated for therapeutic uses in humans. One such
synthetic analog of epibatidine is compound ABT-594 developed by Abbot Laboratories. ABT-
594 is structurally similar to that of epibatidine with a higher affinity to the α4β2 and α3β4
nAChR subtypes (in relation to the other nAChRs) [Boyce S. et al., 2000]. After evaluation of the
compound in studies done with mice proved to be beneficial in pain models such as the formalin
test, spinal nerve
ligation and the hot
plate test researchers
initiated human trials in
patients with diabetic
peripheral neuropathic
pain [Boyce S. et al., 2000;
Rowbotham M. et al., 2009]. Upon conducting the trial, researchers noticed that at administered doses of
ABT-594 150μg to 300μg given twice daily, antinociceptive effects occurred in the tested
samples. This however was complemented with the adverse effects of nausea, vomiting and/or
dizziness in greater than 10% of all the ABT-594 treatment groups within this dose range (see
Figure 2: Phase II clinical outcomes
for ABT-594 in diabetic neuropathy
patients

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patient disposition chart for the study, above) [Rowbotham M. et al., 2009]. Similar outcomes were also
observed when testing compounds ABT-894, TC-2629 and TC-6499 who are primarily selective
to the α4β2 nAChR [Rowbotham M. et al., 2009; Rowbotham M. et al., 2012; Hurst R. et al., 2013]. Thus, this suggests
either that the α4β2 nAChRs mediate some of the interactions which are responsible for the onset
of adverse reactions or that in high concentrations the developed “selective” α4β2 nAChR
agonists interact with other nAChR subunits.
3.1 α7 nAChR Agonists
Despite concerns that the α7 nAChR undergoes rapid desensitization in the presence of
an agonist, research done in the past decade have provided preliminary data supporting the
notion that this subtype of nAChRs is indeed a possible target for achieving
antinociceptive effects [Feuerbach D. et
al., 2009; Umana I. et al., 2013; Damaj M. et al., 2000]. Some receptor modulators of α7 nAChRs which have
become well known through experimental testing include partial agonists GTS-21 and EVP-
6124, the highly selective AR-R17779 and duel acting agonist (α4β2 and α7) A-85308 [Clark R. et al.,
2013]. Using structural components from all four of these compounds, researchers Clark et al.
designed a new class of α7 nAChR modulators by combining their features on a piperazine core
to create the following two generic compounds so that we may be able to observe which
conformational changes cause which effects [Clark R. et al., 2013]. After a series of testing different
functional groups at each position, Clark et al. were able to yield compounds with affinity for the
α7 nAChR. The first compound is oxazolo[4,5-b]pyridine, which is also referred to as R-18, was
Figure 3: Representative α7 nAChR agonists

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created through the attachment of an oxygen atom (O), nitrogen (N) atom and two hydrogen (H)
atoms respective to sites x, y, R1 and R2 in the R-enantiomer configuration [Clark R. et al., 2013].
Through voltage clamp testing with Xenopus oocytes expressing human α7 and α4β2 nAChRs
independently, compound R-18 was shown
to be a potent agonist of the α7nAChR and
have no activity at the α4β2 nAChR [Clark R.
et al., 2013]. The second compound known as
methoxyphenyl urea, referred to here by R-
47, was created through the attachment of
an methoxy functional group (OMe) and two hydrogen (H) atoms respective to sites R1, R2 and
R3 also in the R-enantiomer configuration [Clark R. et al., 2013]. Similar to R-18, R-47 showed to have
no activity at the α4β2 nAChR in voltage clamp testing with Xenopus oocytes expressing human
α4β2 nAChRs. However, when tested on Xenopus oocytes possessing human α7 nAChRs it
failed to elicit a current, signifying that no activity was occurring at the α7 nAChRs [Clark R. et al.,
2013]. Confounded by the results, researchers pretreated the Xenopus oocytes with PNU-120595
[N-(5-Chloro-2,4-dimethoxyphenyl)-N′-(5-methyl-3-isoxazolyl)-urea], a known and well researched type II
positive allosteric modulator for the nAChRs. Compound R-47 was then re-administered and
tested on the Xenopus oocytes expressing human α7 nAChRs, successfully being able to
generate a current [Clark R. et al., 2013]. Given the known actions of PNU-120595, we can classify R-
47 as a “silent agonist” signifying that it is a ligand which can cause the α7 nAChR to enter a
desensitized state through little or no apparent activation of the ion channel [Gronlien J. et al.,2007].
Silent agonists when accompanied by a PAM result in synergistic effect allowing for the
possibility to achieve much more potent effects while at individually low concentrations.
Figure 4: Hybrid ligand for α7 nAChR.
Left: compound R-18. Right: compound R-47

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3.2 α7 nAChR PAMs
PAMs are molecules which bind to their targeted receptors at a distinct regulatory
binding site, the allosteric site, and typically display no activity on their own. By binding to the
non-competitive allosteric site of a receptor, PAMs cause an enhancement to the activity
generated from a ligand that is bound at the orthosteric position, such as that of an agonist. This
characteristic is attributed to a PAM’s ability to diminish the energy required to activate receptor
from its resting state [Damaj M. et al., 2000; Gronlien J. et al.,2007]. PAMs can be further divided into two
distinct types based on the way they achieve this effect. Type 1 PAMs have shown to increase
agonist evoked responses, however do not appear to effect the desensitization properties of the
receptor. In contrast, type II PAMs seem to prolong the activated state of a receptor by
decreasing the desensitization rate caused by the agonist bound in the orthosteric position [Williams
D. et al., 2012].
Although the concept of PAMs have been explored for quite some time, in regards to
benzodiazepines and barbiturates augmentation of the ligand gated ion GABAa receptors, nAChR
PAMs are a relatively new concept [Williams D. et al., 2012]. Calcium ions were among the first known
allosteric modulators of α7 nAChRs. However, much like the other first known examples of
allosteric modulators these lacked in the preferred potency, selectivity or efficacy towards the α7
nAChRs [Williams D. et al., 2012]. CCMI [N-(4-chlorophenyl)-alpha-[[(4-chloro-phenyl)amino]methylene]-3-
methyl-5-isoxazoleacet-amide] a type I PAM of the GABAa receptors was discovered to have
functionality, but partial selectivity, at the α7 nAChRs [Williams D. et al., 2012]. This limits the ability to
distinguish whether the desired effects are in direct response to modulating the α7 nAChRs or
through temperaments in other areas of the body. As a result, NS-1738 [1-(5-chloro-2-hydroxy-

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phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea] a type I PAM for α7 nAChRs which has shown to be
inactive towards α4β2 and α3β4 nAChRs, has been used in several studies to evaluate its
potential in helping treat chronic pain states [Williams D. et al., 2012; Frietas K. et al., 2013; Thakur G. et al., 2013].
When compared directly to the
type II α7 nAChR PAM PNU-120596,
NS-1738 failed to produce the same
nociceptive effects in an experiment using
mice, 6 hours post injury [Frietas K. et al., 2013].
Frieitas et al.’s discovery implies that
although type I PAMs do increase the
activity of agonist mediated responses,
endogenous cholinergic signaling causes
severe desensitization of the α7 nAChRs
which ultimately limit their use. The knowledge gained from this suggests that type II PAMs
may be best suited to potentiate agonist effects at the α7 nAChR since one of its distinguishing
characteristics is that it achieves desensitization at a much faster rate in comparison to the other
nAChRs.
Since then a variety of type II α7 nAChR PAMs have been studied in context of selectivity,
potency and efficacy to determine if they can be used in conjunction with a selective α7 nAChR
agonist to treat chronic pain states. TQS [4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-
cyclopenta[c]quinoline-8-sulfonic acid amide] is a selective type II α7 nAChR PAM very similar in
efficacy and potency when compared to PNU-120596 [Gronlien J. et al.,2007]. Upon testing, both PNU-
Figure 5: Type I & II PAMs for α7 nAChR.

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120596 and TQS proved to be able to reactivate the α7 nAChR from its desensitized state while
eliciting no response from the α7 nAChRs on their own which is congruent with expectations of
a type II PAM [Gronlien J. et al.,2007]. Due to this breakthrough in the functionality and effectiveness of
PAMs, researchers have questioned that if a molecule can possess moderate functional properties
of both type I and type II PAMs (referred to as an “intermediate” PAM; e.g. JNJ1930942, 2-[[4-
fluoro-3-(trifluoromethyl) phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol [Thakur G. et al., 2013]) then couldn’t a
molecule also show to have properties of both an independent agonist as well as a type II PAM
towards the α7 nAChRs.
3.3 α7 nAChR Ago-PAM
Of late, a synthesized substituent analog of the type II PAM TQS was shown to display both
a reduction in the desensitization of the α7 nAChRs as well as agonist effects (Ago-PAM) [Thakur
G. et al., 2013]. Structurally 4BP-TQS, currently the most effective ago-PAM for the α7 nAChRs that
is available, is a compound that contains three chiral centers with the cyclopentene and 4-
bromophenyl rings arranged in a cis- configuration to one another. In comparative studies, ACh
and a racemic mixture of 4BP-TQS (4-(4-bromophenyl) -3a,4,5,9b-tetrahydro- 3H- cyclopenta[c] quinolone-
8-sulfonamide), revealed to produce more effective and potent agonist effects through binding
interactions at a site other than the orthosteric binding position [Thakur G. et al., 2013]. The significance
Figure 6: Improved synthesis of 4BP-TQS and it Enantiomeric Resolution

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of this class of compound is that they have the ability to activate a receptor through an allosteric
binding site as well as potentiate endogenous ACh signaling which is reduced when severe
damage to neurons occurs. However, due to the structural arrangement of this molecule and the
lack of completed research, it was unclear as to whether one or both of the enantiomers
contributed towards this effect.
Very recently, in a study under the supervision of Dr. Thakur and Ph.D candidate Kulkarni
et al., the cis-diasteromer 4BP-TQS was created using expeditious, microwave assisted synthesis
and then separated into its positive and negative rotated enantiomers for functional evaluation
[Thakur G. et al., 2013]. Upon evaluation, it was determined that the negatively rotated enantiomer of
4BP-TQS did not possess the ability to independently produce a response at the α7 nAChRs nor
was significantly able to increase the activity of ACh when co-administered [Thakur G. et al., 2013].
This suggests that (-)-enantiomer of 4BP-TQS-1 is neither effective as an allosteric agonist nor a
type II PAM when targeting the α7 nAChRs. However, in contrast the (+)-enantiomer titled
GAT107 showed significant effects as both an allosteric agonist and as a type II PAM when co-
administered with ACh [Thakur G. et al., 2013]. Further testing also showed that when administered
independently GAT107 attained the ability to potentiate the effects of ACh administered 4
minutes later [Thakur G. et al., 2013]. The work done by Thakur et al. helps provide insight suggesting
that this specific enantiomer of 4BP-TQS could prove to be very useful, either alone or in
conjunction with a α7 nAChR selective agonist, as a clinical agent in the treatment of
neuropathic pain.
4. Conclusion
Through conducting the research required for this topic it is evident that neuropathic pain is a
complex disease state proving difficult to treat and encompasses an unmet medical need. As so,

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the α7 nAChR is emerging as an important target in helping treat neuropathic pain due to its
abundance within the central and peripheral nervous systems as well as its defining
characteristics. In clinical and pre-clinical trials, direct and partial acting α7 nAChRs agonists
have shown to treat neuropathic pain but have been limited in use due to adverse effects and a
small therapeutic window. Type II PAMs, Ago-PAMs and silent agonists may provide novel
therapeutic opportunity. Furthermore, as of recently another proposed idea indicates that
stimulation of the nAChRs contributes to neuroprotective activity that not only treats but can
cure neuropathic pain [Araya J. et al., 2014]. However, at this time it appears that additional
experimentation and research in developing additional α7 nAChR modulators is needed to better
our understanding of the α7 nAChRs functional role in helping treat neuropathic pain.
5. Acknowledgements
The author greatly appreciates the sincerity, support and guidance provided by Dr. Ganesh A.
Thakur and Ph.D candidate Abhijit R. Kulkarni. Together they helped develop a significant
proportion of the material discussed and both their assistance and knowledge was of pronounced
importance.

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Clark R., Lamppu D., Libertine L., et al. (2013) Discovery of novel 2-((pyridin-3-yloxy)methyl)
piperazines as α7nicotinic acetylcholine receptor modulators for the treatment of inflammatory
disorders. Journal of Med. Chem. 57(10):3966-83
Daly J., Garraffo H., Decker M. et al. (2000) Alkaloids from frog skin: the discovery of
epibatidine and potential for developing novel non-opioid analgesics. Natural Products Report.
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an acute pain model. Neuropharmacology. 39(13):2785-91
DʼArcy Y. (2014) Living with the nightmare of Neuropathic Pain. Lippincott Williams & Wilkins
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Feuerbach D., Lingenhoehl K., Olpe H., et al. (2009) The selective nicotinic acetylcholine
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