Current and Emerging Targets To Treat Neuropathic Pain

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J. Med. Chem., 50 (11), 2543 -2546, 2007. Release Date: May 10, 2007

Current and Emerging Targets To Treat Neuropathic Pain

A. Butera

Chemical and Screening Sciences, Wyeth Research CN 8000, Princeton,

New Jersey 08543

Normal pain stimulus, or nociceptive pain, resulting from tissue

damage or an imminent situation that could quickly result in tissue

damage is considered to be a normal physiological response

(feedback) to alert the body that tissue injury has occurred or is

imminent if the appropriate action is not taken. Nociceptive pain

typically responds well to treatment with analgesics and tends to

subside readily when noxious stimuli are removed and/or tissue

damage has healed. In contrast, neuropathic pain involves an

abnormal processing of sensory input usually occurring after direct

injury or damage to nerve tissue. Neuropathic pain is characterized

by a spontaneous hypersensitive pain response and can typically

persist long after the original nerve injury has healed. This

unusually heightened pain response could be observed as hyperalgesia

(an increased sensitivity to a noxious pain stimulus) or allodynia

(an abnormal pain response to a non-noxious stimulus, e.g., cold,

warmth, touch). While nociceptive pain is typically acute in nature

and diminishes upon healing, patients suffering from neuropathic

pain typically endure chronic, debilitating episodes that are

refractory to the current pharmacotherapies and profoundly affect

their quality of life.

It is estimated that neuropathic pain affects over 6 million

patients in the U.S. and Europe and over 26 million patients

worldwide, resulting in a worldwide healthcare cost of over $3

billion per year, with a significant portion of this money paid for

drug therapies that were originally developed for other medical

conditions. Neuropathic pain syndrome is actually a collection of

disorders characterized by different etiologies including infection,

inflammation, disease, trauma or compression to major peripheral

nerves, and chemical or irradiation-induced nerve damage. The nerve

tissue lesion may be found in the brain, spinal chord, or the

peripheral nervous system. Clinically, chronic neuropathic pain has

been associated with the following medical conditions: lumbar

radiculopathy (lower back pain caused by disk compression or

herniation), spinal chord injury, phantom pain, diabetic neuropathy,

postherpetic neuralgia, and in some patients fibromyalgia and cancer-

related pain.

As physicians are faced with an increasing number of patients with

numerous neuropathic pain symptoms most likely stemming from

multiple etiologies, they are forced to resort to the polypharmacia

approach as the mainstay therapy. Current pharmacological treatment

for neuropathic pain will typically include some combination of

agents from several of the following drug classes: opioids,

tricyclic antidepressants, anticonvulsant agents, or nonsteroidal

anti-inflammatory drugs (NSAIDs)/analgesics. Ironically, even with

such an impressive arsenal of powerful drugs, these approaches only

provide an approximate 30-50% reduction in pain in about 50% of

patients. Coupled with this limited efficacy, there are low levels

of compliance due to intolerable side effect profiles associated

with some of these drugs. These results profoundly illustrate that

treatment of neuropathic pain is a hugely unmet medical need, and

they underscore the importance of considering, validating, and

pursuing alternative targets to treat refractory neuropathic pain.

This Miniperspective series of manuscripts will focus on newer

developments in medicinal chemistry advances toward treating

neuropathic pain. It will provide focused reviews of emerging

targets by the experts in this field of research and, in doing so,

will offer a snapshot of the current status of research within each

of these drug classes. The following Miniperspective, authored by

Kennedy of Wyeth Research, will provide a pharmacological

overview of neuropathic pain. The main focus of this paper is to set

the backdrop for the rest of the series by describing the etiology

of this complex medical syndrome and dissecting the distinguishing

properties of each type of pain sensation: nociceptive,

inflammatory, and neuropathic pain. The paper will then focus on the

underlying signaling mechanisms and molecular mediators or targets,

which play key roles in pain propagation. In an attempt to tease

apart the formidable complexity of debilitating neuropathic pain

syndrome, the paper exposes a plethora of potential targets that

have been pursued, some with modest success and others yet that hold

continued or renewed promise as advances are made in our

understanding of the physiology and pharmacology of pain.

While excitatory amino acids are crucial to normal physiological

processes such as learning, memory, and cognition, they have been

implicated to play an important role in the development and

propagation of nociceptive and neuropathic pain signaling. The N-

methyl-D-aspartate (NMDA) receptor, a ligand-gated ion channel

comprising multiple protein subunits coupled with other proteins to

provide a variety of regulatory sites including glutamate, glycine,

polyamine, Mg2+, and PCP binding sites, is an ionotropic receptor

for L-glutamate. In animal models, blocking the NMDA receptor has

also been shown to prevent the development of tolerance to opioid-

mediated analgesia, thereby suggesting a potential benefit to

coadministration of NMDA receptor antagonists with opioids. In the

target-related Miniperspective, Wayne Childers and Reinhardt Baudy

of Wyeth Research review the recent advances in the NMDA receptor

antagonist pipeline for the treatment of neuropathic pain. Because

of the complex nature of this receptor with a large number of

regulatory subunits and a plethora of binding sites where an

antagonist could interact, the NMDA receptor provides an unusually

high number of attractive molecular targets for medicinal chemists

to pursue. This review will focus on the varied strategies and

rationale for pursuing compounds that act at specific sites on the

NMDA receptor, both in the periphery and in those centrally located,

as well as on the challenges scientists have met so far and the

shortcomings of some of the most advanced NMDA receptor antagonists.

While glutamate-based efforts in neuropathic pain have focused

mostly on ionotropic receptors like NMDA, AMPA, and kainate, recent

focus has shifted to metabotropic glutamate receptors. On the basis

of sequence homology, differential signal transduction mechanisms,

and overall pharmacological profiles, the metabotropic glutamate

receptors (mGlu1-8) have been classified into three groups: (i)

group I receptors (mGlu1 and mGlu5), (ii) group II receptors (mGlu2

and mGlu3), and (iii) group III receptors (mGlu4 and mGlu6-8). The

role of group I receptors (positively coupled to phospholipase C) in

pathophysiological processes such as pain signaling, neuronal

excitability, and nociception has been investigated. Expression of

mGlu1 receptors to areas of the central nervous system (CNS) and

periphery associated with pain propagation has made this an

attractive target for chronic pain management. Antagonists of mGlu1

receptors have been shown to be effective in numerous models of

epilepsy, neurodegeneration, and neuropathic pain. In their

manuscript, Schkeryantz and colleagues describe and contrast

two bodies of research on competitive and noncompetitive mGlu1

antagonists. While the earlier competitive mGlu1 antagonists based

on constrained analogues of glutamic acid gave rise to several

classes of amino acids with impressive subtype selectivity, their

lack of oral activity has precluded their further development.

Characterization of numerous classes of non-amino acid based

noncompetitive mGlu1 antagonists has recently led to potent druglike

leads with the potential for improved overall pharmaceutical

profiles. Whether these molecules will provide better clinical

candidates remains to be seen.

In addition to the reported progress in the field of ligand-gated

ion channels, the voltage-gated ion channels continue to represent a

significant body of research in the neuropathic pain arena. These

families of diverse transmembrane spanning proteins acting as

molecular conduits for the translocation of anions (Cl-) and/or

cations (Ca2+, K+, Na+) in or out of cells play a key role in the

regulation of cell membrane excitability, synaptic release of

neurotransmitters, and overall generation and propagation of pain

signaling. The next three manuscripts are illustrative of recent

medicinal chemistry advances in the fields of three " families " of

cationic channels and how newly designed ligands of these channels

may offer new opportunities to effectively treat neuropathic pain.

Gabapentin (Neurontin) (1-(aminomethyl)cyclohexaneacetic acid) is

considered by physicians to be the " gold standard " treatment for a

variety of neuropathic pain. It is prescribed to over 50% of

patients suffering from diabetic neuropathy or postherpetic

neuralgia. The drug is well tolerated except for sedation seen at

higher doses. Its rather cumbersome dosing regimen (three to four

times daily) limits its broader use however. With the recent launch

of the follow-on compound pregabalin ((S)-3-(aminomethyl)-5-

methylhexanoic acid) in the U.S. and Europe, Pfizer has positioned

itself at the forefront of the neuropathic pain arena. As a 3-

substituted analogue of -aminobutyric acid (GABA), pregabalin

(Lyrica) offers a much-improved pharmacokinetic profile over

gabapentin showing a bioavailability of 90%, thus allowing for a

more acceptable dosing regimen. Although their mechanisms of action

are not totally clear, compounds represented by gabapentin and

pregabalin are thought to exert their effects of blocking

neuropathic pain by binding to the 2- subunit of voltage-gated Ca2+

channels. This interaction results in inhibition of calcium influx

into neuronal cells, thereby inhibiting neurotransmitter release and

suppressing the development of central sensitization. Schwarz

and colleagues outline recent advances in the medicinal chemistry of

potent 2- ligands. In their Miniperspective, they track lead

progression from the -amino acid class of 2- ligands typified by

gabapentin and pregabalin to structural variants in the -amino acid

and -amino acid classes and then finally to newly discovered non-

amino acid leads and prodrugs. In vivo activity associated with this

class of molecules is usually only realized if the compound is a

substrate for the system L amino acid transporter. The review nicely

points out compounds that are potent in vitro ligands but yet fail

to demonstrate efficacy in neuropathic pain models because of their

low affinity for the system L transporter. The tendency for spiro-

lactonization within the -amino acid class of ligands prompted the

Pfizer scientists to evaluate and develop numerous carboxylic acid

bioisosteres that are reviewed and shown to potently inhibit [3H]

gabapentin binding to the 2- subunit. Binding affinity was found to

correlate well with the acid pKa value. Highlighted compounds were

shown to be active in the footpad incision model of neuropathic

pain. The inactivity of highlighted leads in R217A mutant mice

lacking the 2- subtype supports the mechanism of action of this

compound class. Finally, the paper reviews recent evidence that

suggests that 2--1 and 2--2 subunits are differentially expressed

throughout the CNS, possibly providing encouragement for pursuing a

subtype selective ligand that may provide an improved side effect

profile.

Recent data have emerged that support the role and function of the

KCNQ K+ family of channels (Kv7) in the regulation of neuronal

excitability and nociception. All KCNQ channels can couple to

muscarinic receptors and form M-currents that are gated (inhibited)

by acetylcholine. Their localization in the CNS, spinal chord, and

dorsal root ganglion makes them an attractive target for the

treatment of neuropathic pain. In their Miniperspective, Gordon

Munro and Dalby-Brown from NeuroSearch A/S present an

overview of Kv7 channel openers and their effectiveness in numerous

neuropathic pain models. Originally developed as an antiepileptic

agent, the prototypical Kv7 channel opener retigabine (ethyl [2-

amino-4-[[(4-fluorophenyl)methyl]amino]phenyl]carbamate) and its

analogues have been shown to attenuate neuropathic and nociceptive

pain behaviors in several rodent models. Electrophysiological

studies have shown that these compounds potently hyperpolarize

neuronal cells. These hyperpolarization effects have been shown to

be sensitive to linopirdine (1,3-dihydro-1-phenyl-3,3-bis(4-

pyridinylmethyl)- 2H-indol-2-one) and XE-991 (10,10-bis(4-

pyridinylmethyl)- 9(10H)-anthracenone), known blockers of the Kv7

family, thus suggesting involvement of these channels. The paper

then introduces " second-generation " Kv7 ligands that differ in

structure from the troublesome " trianiline " scaffold featured in

retigabine. In addition to improved selectivity profiles favoring

Kv7.2 and Kv7.3 channel subtypes and their more druglike features,

these newer molecules may offer an improved safety profile over the

first-generation Kv7 openers developed for epilepsy.

Multiple classes of drugs that have historically been associated

with pain relief, including anticonvulsants, antidepressants, and

class I antiarrhythmics, make up the third family of cation-channel

modulators addressed in this series, the sodium channel blockers.

Don and Victor Ilyin of Purdue Pharma L.P. provide a

Miniperspective on how historical Na+ channel blockers have shown

utility in numerous preclinical and clinical pain studies. With the

recent cloning of Na+ channel subtypes and numerous subunits, the

underlying role and function of these pore-forming proteins are

becoming better understood, thereby leading to the identification of

molecules that interact differently with the channel or to different

states of the channel (open, inactivated, or resting states). This

has opened exciting opportunities for the potential characterization

of Na+ channel blockers with optimized subtype selectivity profiles

and overall pharmacological properties.

Since the discovery that capsaicin (N-[(4-hydroxy-3-methoxyphenyl)

methyl]-8-methyl-(6E)-6-nonenamide), a pungent natural product

derived from hot chilli peppers, alleviated pain sensations after

topical applications, its mechanism of action has been the focus of

much research. It has since been shown to be a potent agonist for

the transient receptor potential channel, vanilloid type 1 (TRPV1).

In the final manuscript in this Miniperspective series,

Westaway of GlaxoKline provides a concise survey of the recent

primary and patent literature of newly developed modulators of TRPV1

for the treatment of neuropathic pain. TRPV1 is a member of a family

of nonselective, ligand-gated ion channels predominantly located on

primary afferent nociceptors in DRG. In addition to sensitivity to

capsaicin and its more potent analogue resiniferatoxin, TRPV1 is

also activated by an acidic environment and heat, thereby triggering

cellular Ca2+ influx, causing subsequent depolarization,

excitability, neurotransmitter release, and propagation of pain

signals. Paradoxically, both TRPV1 agonists and antagonists have

been shown to demonstrate efficacy in various animal models of

neuropathic pain. Thus, topical application of capsaicin cream,

while initially producing an uncomfortable burning sensation,

eventually leads to analgesia due to the persistently high

intracellular Ca2+ levels that subsequently desensitize the

nociceptors fibers causing degeneration of pain signaling. A high-

dose (8%) capsaicin transdermal patch (NGX-4010), currently being

developed for the treatment of HIV related neuropathic pain and

postherpetic neuropathy, might offer an advantage over the cream

applied capsaicin. Of greater potential utility is the development

of a plethora of newly identified TRPV1 antagonists for neuropathic

pain. The prototypical TRPV1 antagonist capsazepine, a compound

related to capsaicin that has been shown to block capsaicin-mediated

behaviors in rodents, has become an invaluable tool for studying the

effects of TRPV1 antagonists in neuropathic pain models. Attempts to

improve on the poor physical properties associated with the

capsazepine scaffold have led to a large number of urea, thiourea,

and amide structures as potent and useful TRPV1 antagonists.

Evidence is mounting that TRPV1 is also expressed in other areas of

the CNS such as the brain, as well as outside the CNS such as in the

GI system, lung, and bladder. With the availability of both agonists

and antagonist tool ligands, the future utility of TRPV1 modulators

may quickly spill outside the neuropathic pain arena.

While an exhaustive treatise of emerging approaches to treat

neuropathic pain is virtually impossible in a venue of this type,

the six molecular targets reviewed in this Miniperspective series

(NMDA, mGlu1, Ca2+ channels, K+ channels, Na+ channels, and TRPV-1)

are illustrative of the most active fields of research and hopefully

represent some of the more promising strategies for discovering more

effective and safer pain medications to meet the challenges of the

future. According to opinion leaders, improved efficacy remains as

the most significant underserved need in the neuropathic pain

markets. Current pharmacologic treatments for neuropathic pain

syndromes struggle to achieve a maximum of 50% reduction in overall

patient pain scores. Trying to push beyond this level of relief by

using higher doses of currently available drugs is typically

fruitless because of intolerable side effects. A newly approved pain

drug could easily achieve " blockbuster " status by merely exceeding

this apparent efficacy ceiling, even while maintaining the same side

effect profiles and dosing regiments of current therapies. However,

the impact of a more efficacious pain drug that introduces other,

more serious side effects will most likely be diminished. A

neuropathic pain drug with the right balance of potency, efficacy,

pharmacokinetics properties, and safety profile would clearly make a

significant impact on the quality of life of millions of patients.

J. Triggle, the Perspective Editor for the Journal of

Medicinal Chemistry up to March 31, 2006, proposed the idea of this

Miniperspective series on neuropathic pain following a session

sponsored by the Division of Medicinal Chemistry at the 230th

National Meeting of the American Chemical Society held in

Washington, D.C., in the Fall of 2005. I am grateful to have had the

opportunity to work with Dave on this project as we set the tone by

inviting these distinguished contributors. I am equally grateful to

Greenlee, the current Perspective Editor for the Journal of

Medicinal Chemistry, who provided a seamless transition from Dave

and key leadership that facilitated the process of completing this

project in a timely manner. Most importantly, we extend our

gratitude to the contributors to this Miniperspective series on

neuropathic pain. We thank them for their time and dedication in

providing excellent reviews and making this a successful project.