Current Therapeutic Targets for Neuropathic Pain:

Derivatives of sulphonamides:

Analgesic Activity of Acyl-sulfonamides:

GX-201 was dosed orally, and followed by subcutaneous aconitine injection into the dorsum of the hind paw. The NaV1.7-selective acylsulfonamide (GX-201) displayed dose dependent efficacy in the IEM (Immuno-electron microscopy) assay across aconitine-induced pain. This compound exhibited a similar dose-dependent inhibition of aconitine-induced nociceptive events at higher plasma concentrations^1,12.

Analgesic Activity of Aryl-sulfonamides:

A selective arylsulfonamide antagonist of NaV1.7, PF-05089771 was approved by Pfizer for analgesic activity with patients having inherited erythromelalgia. The likely explanations for the difference in efficacy between acyl- and arylsulfonamides fall into three categories, inaccurate measures of IC₅₀or free fraction, Tissue distribution and access to binding site is more favorable for acylsulfonamides, and Acylsulfonamides have a significantly longer residence time on NaV1.7, resulting in greater efficacy¹³.

Cannabinoid receptors (Exogenous cannabinoids):

Cannabinoid receptors (CB1 and CB2) have been associated to pain modulation, receptor activation may causes pain. Exogenous cannabinoids are involved in the analgesic mechanisms of medications commonly account for Neuropathic pain. Cannabinoids can be divided into four different groups. The first group includes the classical cannabinoids, which consist of natural cannabinoids (such as THC) and synthetics (such as HU-210)¹⁴. Tetrahydrocannabinol (THC) is the component in cannabis responsible for its therapeutic effects. Another component, Cannabindiol (CBD), has an additive effect. The second group contains non classical cannabinoids; CP-55 is a nonspecific cannabinoid receptor agonist. The third class consists of aminoalkylindoles, which are synthetic cannabinoids such as AM1241. Diarylopyrazoles form the fourth group, which collectively consists of specific cannabinoid receptor antagonists, where SR141716A is a representative ¹⁹. Exist literature suggest that targeting the endocannabinoid system for prevention and treatment of CINP (Chemotherapy induced neuropathic pain) and antiretroviral-drug induced neuropathic pain is a plausible therapeutic option^15-18.

Angiotensin II type 2(AT₂) Receptor:

AT₂receptor antagonists represent a completely new class for targeting and designing of drugs ². EMA 401 is orally active, highly selective, peripherally restricted AT₂ receptor antagonist that has been successful in a clinical proof of concept trial phase II in patients with post therapeutic neuralgia. EMA 40 has been demonstrated and found to be effective in a clinical trial in post therapeutic neuralgia. Although it is still in the preclinical phase, studies show promising results of stem cell treatment for neuropathic pain¹⁹.

Imidazoline- 2 (I₂) Receptor:

Literature search reflects, molecules targeting imidazoline-2 (I₂) receptors could be a novel class of analgesics. I₂ receptors are widely dispersed in mammalian cells and tissues, particularly in the central and peripheral nervous system. On the other hand nature and signaling pathways of I₂ receptors is not fully understood. They allosterically regulate the activity of enzymes tangled in brain energy requirements and the monoaminergic descending pathways of pain control. CR4056 is a reversible and specific I₂ ligand, as determined in a broad characterization panel in vitro. Oral CR4056 shows a potent, dose response analgesic activity in different animal models of nociceptive and neuropathic pain. In addition, the compound has a strong opioid-like activity and prevents tolerance to morphine similarly to I₂ agonist tool compounds. CR4056 was extensively studied in phase 1 clinical studies, where it proved to be safe and well tolerated. The compound is now in phase 2 clinical development as a non-opioid analgesic for the treatment of acute and chronic pain. CR4056 is a non-opioid analgesic in knee Osteoarthritis patients with moderate to severe chronic pain and different phenotypes. Most common adverse event is headache and is reported in 13% population^20,21.

Lymphocyte function associated antigen 1 (LFA-1):

A potential therapeutic approach was examined with the goal of controlling proinflammatory responses in neuroanatomical regions critical for chronic constructive injury (CCI) induced allodynia by blocking LFA-1 actions using BIRT377. The small molecule, (R)-5-(4-bromobenzyl)-3-(3, 5-dichlorophenyl) - 1, 5-dimethyl imidazolidine-2, 4-dione (BIRT377) is a low molecular weight non-ionic compound. It avoids the conversion of LFA-1 into its high-affinity conformation through non-covalent binding to the CD11a chain, which is a component of LFA-1. So, upon BIRT377 binding to LFA-1, circulating leukocyte cell adhesion, infiltration and migration to sites of inflammation are prevented BIRT377 is highly selective for LFA-1²².

FAAH and MAGL: (Fatty acid amide hydrolase and Mono-acyl glycerol lipase):

FAAH is the AEA hydrolyzing enzyme which is an integral membrane enzyme. Fatty acid amide hydrolase (FAAH) is an enzyme that hydrolyzes the endocannabinoid anandamide, 2-Arachidonoyl glycerol and related amidatedsignaling lipids. FAAH inhibitors are of two types reversibly (e.g., trifluoromethyl ketones; α-ketoheterocycles) and irreversibly (e.g., fluorophosphonates; carbamates; ureas) acting agents. Several FAAH inhibitors have various mechanisms to inhibit FAAH and have different chemistry from one another. FAAH and MAGL has simplified the functional investigation of AEA and 2-AG signaling pathways, respectively. The dual FAAH/MAGL inhibitorJZL195 provides a powerful pharmacological probe to assess the behavioral impact of simultaneous elevations in the two principal endocannabinoids AEA and 2-AG²³. They have designed dual FAAH/MAGL inhibitors based on an electrophilic N-carbonyl piperidine/piperazine structural motif common to both the MAGL-selective inhibitor JZL184, and the FAAH-selective inhibitors PF-622 and PF-3845. JZL195 also inhibited rat and human FAAH and MAGL enzymes with IC50 values in the range of 10–100 nM. It also inhibits endocannabinoid hydrolysis and elevates 2 AG and AEA level in vivo. A number of authors have believed that selective FAAH inhibitors, such as URB597, OL-135, PF-3845, PF- 04457845 and ST-4070 reduce the mechanical and cold allodynia induced in a range of animal models of chronic pain. These all drugs can be categorized under the category called novel endocannabinoid modulator²⁴.

Substrate-derived inhibitors:

The trifluoromethyl ketone analogue of oleamide was displayed to be a potent inhibitor of this enzymatic activity (Ki = 82nM). The enzyme capable for the hydrolysis of AEA and oleamide was analyzed and characterized from studies using trifluoromethyl ketone analoguewhere a thiol was introduced at the terminus of the acyl chain and linked through a disulfide bond to beads. Another prominent substrate-derived inhibitor is MAFP, Substrate-based inhibitors have provided useful chemical tools, but they are not viable templates for drug design because they are highly hydrophobic and have low selectivity²⁵.

Monoglyceride Lipase (MGL):

MGL-deficiency is related with decreased CB1 receptor density, reduced CB1 receptor ligand binding, and resistance to the hypometabolic effects of CB receptor agonists i.e. simply, CB receptor desensitization. MGL blockade tends to CB receptor desensitization. One of the first selective inhibitors developed was JZL184 which inhibits MGL by irreversible active site carbamylatio. JZL184 inhibits around 90% of 2-AG hydrolase activity in the brain and results in strong accumulation of 2-AG and other MGs 30 min after administration. However, MGs did not elevate in all tissues which could either indicate that MGL activity is committed by other MG hydrolase in certain tissues or that JZL184. The orally active MGL inhibitor SAR127303 has been believed to have anti-nociceptive properties, and it was accepted that even with repeated administration no tolerance caused since the effects were maintained in the formalin test. Administration of the highly selective MGL inhibitor KML29 produces analgesia without cannabimimetic side effects, its chronic administration, however, results in CB1 receptor desensitization, as similarly observed for other MGL inhibitors²⁶.

Electrophilic ketone inhibitors:

Electrophilic ketone inhibitor like α-ketoheterocycle (OL-135) is a highly selective inhibitor but In-Vivo results produce only transient elevations in AEA. Different modification in the chemical structure of parent molecule can results in production of significantly higher activity novel molecules. The incorporation of a nitrogen into the benzoxazole resulted in oxazolopyridine, which increased the potency > 50-fold (Ki = 2.3 nM). These compounds showed higher potency (Ki = 0.2 – 0.3nM) and were much more favorable to further structural modification. Efforts to optimize the heterocycle resulted in the unfused pyridyl oxazole. OL-135 exhibited > 10,000-fold selectivity for FAAH over KIAA1363 and 60-fold selectivity over triacylglycerol hydrolase. The potency further was recovered and the selectivity was increased with pyridyloxadiazole (Ki = 0.29 nM). The electrophilic character of the ketone should prove to be critical for FAAH activity. Boger et al. have further developed a series of oxazoles with small substituent for the same targets. Series of oxazoles with small substituent and showed that FAAH inhibition potency tracked with the electron-withdrawing potential of the R group which shows might be the potential molecules in clinic for neuropathic pain. Like wise Series of ketooxazole FAAH inhibitors in which they have introduced a piperidine into the acyl side chain resulting in increased solubility which effective in increasing bioavailability of drugs. Another class of drugs such as reversible inhibitors α-ketoheterocycle OL-135has been found to display good in vitro potency and selectivity for FAAH relative to other serine hydrolases in mammalian proteomes. FAAH inhibitors may prove to be potential candidates for the treatment of nervous system disorders^27,28.

Carbamate inhibitors:

URB532 and URB597 are the examples of carbamate inhibitors discovered by Piomelli and colleagues. These drugs raised endogenous brain levels of anandamide and other NAEs approximately 3–5 fold and produced CB1-dependent anxiolytic and analgesic effects ¹⁰. The first carbamate inhibitors of FAAH were designed by modulating the structure of a known inhibitor of the serine hydrolase acetyl cholinesterase. The 5- fold improved potency was shown by meta-biphenyl derivative (IC50 = 63 nM) and addition of an amide on the biphenyl resulted in a further 10-fold increased potency to give URB597 (IC50 = 4.6 nM) [29]. Arguably, the well-studied FAAH inhibitor to date is URB597, an irreversible inhibitor of FAAH with high selectivity in the nervous system. However, URB597 shows some notable shortcomings, including the inactivation of other serine hydrolases in peripheral tissues. By replacing the cyclohexylring of with β-naphthylmethyl ring gives URB880 which also responsible for further increase in potency. Later, Cravatt and Alexander prepared a hybrid of OL-135 and URB597 in which the cyclohexyl was removed and further replaced with phenhexyl to give JP83. Later, the design of a ‘clickable’ carbamate activity-based probe (JP104) is done to display the proteome reactivity of FAAH-directed carbamates in vivo. These compounds could be categorised into two general classes, aryl/heteroaryl alkyl carbamate as exemplified by SA-47 and piperazine/piperidine carboxylates shown by compound. The corresponding N-ethyl carbamate and urea analogue were inactive because it was proved that the phenyl carbamate is functioning as an electrophile resulting in covalent modification of FAAH. Irreversible phenyl carbamate inhibitors, such as URB597, inactivate other hydrolases in peripheral tissues, including several carboxylesterases. 2-(Methylamino)-2-oxoethyl carbamates SA-47 seem to be more selective for FAAH than the phenyl carbamates²⁹.

Urea inhibitors:

Urea inhibitor, PF-3845 selectively inhibits FAAH in vivo and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH’s serine nucleophile. Since 2006, Takeda, Johnson and Johnson, Pfizer, and Astellas have reported piperazine/piperidine aryl ureas as a rising class of FAAH inhibitors. In 2007, Pfizer presented the Scripps Research Institute reported that the quinolinepiperidine urea PF-750 inhibited FAAH in a time-dependent manner. PF-750 selectively inhibited FAAH relative to other mammalian serine hydrolases as determined by ABPP (Activity Based Protein Profiling). More recently, a series of biaryl ether urea analogues with boost in potency have been reported. PF-3845 is also one of the most potent inhibitor. In addition, the trifluoromethyl group of moleculewas replaced with an alkyne to generate ‘clickable’ ABPP probe that was used to profile the in vivoselectivity of this inhibitor. Given the covalent, irreversible inhibition of FAAH, the potency of irreversible inhibitors was measured by the second order rate constants are the best analysis of potencies of irreversible inhibitors³⁰.

Boronic acid inhibitors:

Recently, Infinity has discussed a series of aryl boronic acids as inhibitors of FAAH in a patent application. It is hypothesized that the boronic acids form a reversible covalent complex with the active site serine nucleophile of FAAH and the aryl ring is directed toward the hydrophobic acyl chain-binding channel. Publication from the University of Kuopio in Finland has also reported a series of boronic acid FAAH inhibitors with alkenyl boronic acid being the most potent (IC50 = 14 nM). Boronic acids have previously been reported as covalent inhibitors of serine proteases, and so it will be important to assess the selectivity of these compounds against miscellaneous serine hydrolases. In near future this target can be a potential target for neuropathic pain drug development³¹.

Interleukin-17 (IL-17):

The proinflammatory cytokine interleukin-17 (IL-17) is implicated in pain regulation. However, the synaptic mechanisms by which IL-17 regulates pain transmission are unknown.IL-17 suppresses inhibitory synaptic transmission by inhibiting GABA-receptor-mediated currents. In the DRG (dorsal root ganglion), IL-17 increases neuronal excitability and IL-17R contributes to paclitaxel-induced nocicepto hyperactivity. IL-17 mediates paclitaxel-induced neuropathic pain by T-cell-independent mechanism. IL-17 regulates pain via neuron-glial interactions both in the spinal cord and DRG. Over expression of IL-17 in spinal astrocytes induces mechanical allodynia. Here, we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in the spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. Recently, IL-17 was found to regulate inflammatory responses associated with neuropathic pain induced by nerve injury. IL-17 levels are upregulated in injured nerves in neuropathic pain models. Here, they investigated that IL-17 and IL-17R modulate excitatory and inhibitory synaptic transmission of SOM+ excitatory neurons in normal and pathological pain conditions, and we further tested the involvement of IL- 17/IL-17R signaling in the paclitaxel-induced neuropathic pain model³².

MT1/MT2 receptors (Melatonin Receptor 1 and 2):

Melatonin (MLT) and its analogs are gaining attention in the recent years due to their protective properties against various injuries to the nervous system. Accumulating data indicate that MLT plays a key role in numerous physiological processes including circadian rhythm regulation, body mass index maintenance reproduction, immune responses, neuroprotection, and cardio protection.MLT is also known to have strong antitumor, anti-inflammatory, and anti-oxidant effects. MLT is now being considered as a potential candidate for future adjuvant, in combination with opioid drugs for treating chronic pain conditions. In addition to MLT recently many MT2 agonists were approved to for the treatment of depression and insomnia. The anti-allodynic effects were blocked upon administration of non-selective opioid receptor antagonist naloxone and MT1/MT2 antagonist luzindole. It is reported that intrathecal administration of MLT can reduce the intensity and length of capsaicin-induced allodynia and hyperalgesia resultant from capsaicin injection. 8-Methoxy-2-propionamidotetralin (8MPDOT), N-{2-[(3- methoxyphenyl) phenylaminoethylacetamide (UCM765), N- {2-([3-bromophenyl]-4-fluorophenylamino) ethyl acetamide (UCM924) and N-[(1-benzyl-1,2,3,4-tetrahydro-5-methoxyquinolin-2-yl) methyl] propionamide (UCM1014) and iik-7 N Butanoyl 2-(9-methoxy-6H-iso-indolo[2,1-a]indol-11-yl)- ethanamine are some of the recently developed MT-2 agonists⁴.Some of the reported MT-2 agonists were known to be very effective in the management of neuropathic pain with several benefits over MLT and comparative effects to that of clinically approved analgesic³³.

Voltage-gated sodium channels:

(Na_vs or VGSCs) are a family of transmembrane proteins that plays an important role in electrical signaling of cells in various tissues. Nine isoforms of Na_v channels have been identified to date, nomenclated Na_v1.1 to Na_v1.9 ³⁴. We will discuss these channels in more detail in below table.

The rationale for targeting a specific subtype of sodium-channel blocker for the treatment of chronic neuropathic pain is to avoid side effects associated with activity on other Na_v subtypes, or possibly even other receptor classes. Most Na_v blockers currently used for pain management are nonselective;these drugs are known for their narrow therapeutic index and multiple serious adverse effects due to their action on Na_v subtypes in the CNS and the heart, such as dizziness, sedation, convulsions, and cardio toxicity. When considering the selectivity profile of a safe Na_v blocker for management of pain, one must keep in mind expected side effects based on expression patterns^35,36.

Table 2: Different sodium channels and their tissue expression³⁴

Subtype	Gene	Tissue expression
1.1	SCN1a	CNS
1.2	SCN2a	CNS
1.3	SCN3a	Mainly expressed during embryonic development, but upregulated in adult sensory nerves and DRG neurons after nerve injury
1.4	SCN4a	Skeletal muscle
1.5	SCN5a	Heart muscle
1.6	SCN8a	CNS, DRG neurons, large motor and sensory neurons
1.7	SCN9a	Olfactory sensory neurons, sensory neurons, pancreatic β-cells, skin, DRG neurons
1.8	SCN10a	Retina, sensory neurons, heart muscle, skin, DRG neurons
1.9	SCN11a	Retina, sensory neurons, DRG neurons

Table 3: Novel therapeutic targets (in clinical trials) for neuropathic pain^37,38

Drug	Company	Mechanism	Phase	Indication
Prialt (ziconotide)	Elan/ Eisai	N-type Ca-channel blocker, intrathecal	Launched	Severe chronic pain
Lacosamide (Vimpat, Harkoseride)	SchwarzPharma	Nav block	Phase 3	Positive in PDN. Evaluation in fibromyalgia and OA ongoing
Topamax topiramate	JandJ	Glut antag/ GABA agonist/ Nablocker	Phase 3	Launch for epilepsy and migraine.
XP13512	GSK/ Xenoport	Pro-Gabapentin	Phase 2	Recruiting Phase 2
TC6499	GSK/ Targacept	Neuronal nicotinic receptorAgonist	Phase 1	Recruiting Phase 1
Retigabine	Valeant	Potassium channel KCNQ2/3opener	Phase 3	Efficacy in epilepsy
NGD8243 (MRK2295)	Merck	TRPV1 antag	Phase 2	Postoperative dental pain
Transacin (Transdolor, NGX-4010) (topical)	NeurogesX	TRPV1 agonist (capsaicin)	Phase 3 (HIV)	Pain reduction in HIV
Sativex, GW-1000, Buccal spray	GW Pharma	Cannabinoid-receptor agonist	Phase 3, Phase 2 in PDN	Approved for cancer and MS pain. Effective in NP with allodynia
IP 751, CT-3, ajulemic acid	Indevus	CB1 receptor-agonist/CoX-2/IL-1 Block	Phase 2	Reduces spinal and nerve injury pain
KDS2000 (topical)	Kadmus Pharma	Cannabinoid	Phase 2	Progress in PHN and PDN
AZD 1940	Astra Zeneca	Cannabinoid-receptor agonist	Phase 2	In progress
TRO-19622 (oral)	Trophos	Unknown	Phase 2a	Recruiting PDN patients
AMG403	Amgen	Anti-NGF mAb	Phase2 starting	------
SB-509	Sangamo	Plasmid DNA to up-regulate VEG-F	Phase 2 (PDN)	Disease modifying for diabetes

CONCLUSION:

In conclusion, Neuropathic pain is a most common problem in the today’s society. There are several treatment options for it. But keeping severity of pain in mind new molecular targets need to explore. In the current review we elucidated several targets proteins which can plays a key role in neuropathic pain for development of new molecules. By reading the entire articles summary we came to conclusion that different targets, Cannabinoid receptors (CB1 and CB2) have been associated to pain modulation, receptor activation may causes pain, AT₂receptor antagonists represent a completely new class for targeting and designing of drugs, I₂ receptors could be a novel class of analgesics, Lymphocyte function associated antigen 1 (LFA-1) is a potential therapeutic approach, The dual FAAH/MAGL inhibitor JZL195 provides a powerful pharmacological action and Electrophilic ketone inhibitor like α-ketoheterocycle (OL-135) is a highly selective inhibitor, these are the crucial protein targets. If we modulate them we can overcome conditions like neuropathic pain.

CONFLICT OF INTEREST:

The authors have no conflicts of interest.

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Received on 18.08.2021 Modified on 02.11.2021

Asian J. Pharm. Res. 2022; 12(1):96-104.

DOI: 10.52711/2231-5691.2022.00015

Exogenous Cannabinoid	Influence on Endocannabinoid system	Effect in pain
A-836, A-339	Cannabinoid 2-R agonist	CB2-R-mediated anti-hyperalgesic effect in Freund’s adjuvant model of inflammatory pain; analgetic in the Chronic constriction injury model (CCI), skin incision, and capsaicin-induced hyperalgesia models.
GW-405833	Cannabinoid 2-R agonist	Reduction of mechanical allodynia and glial activation in long-term treatment in neuropathic rats.
OL-135	Reversible FAAH inhibitor	Decrease of mechanical allodynia and acetone-induced cold allodynia in mice CCI model.
PF-3845	FAAH inhibitor	Attenuation of mechanical and cold allodynia in wild-type mice in CCI model.
URB-602	MAGL inhibitor	Elevation of 2-AG level in the dorsal midbrain and enhancement of Anti-nociception in SIA model.
SR141716A	Cannabinoid 1-R antagonist	Prevention of antiallodynic properties of WIN55, 212-2 in rat SNL model; blockage of HU210-induced attenuation of increased locomotor activity.
SR-144528	Cannabinoid 2-R antagonist	Prevention of antiarthritic effects of CB2-R agonists in CIA model in chronic administration.
URB-597	Irreversible FAAH inhibitor	Potentiation of antinociception after injection into the dorsolateral PAG in SIA model; elevation of PAG anandamide and 2-AG level safter intra-PAG injection in healthy rats and decrease of mechanical allodynia and acetone-induced cold allodynia in mice CCI model.
WIN-55, 212-2	CB1-/CB2-R agonist	Alleviation of thermal and mechanical hyperalgesia in CCI model and effectivness against thermal hyperalgesia and mechanical allodynia in SNL model.