α4β2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain

European Journal of Pharmacology 712 (2013) 22–29

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Review

α4β2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain Ramakrishna Nirogi n, Venkatesh Goura, Renny Abraham, Pradeep Jayarajan In-Vivo Pharmacology, Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road No. 5, Avenue-7, Banjara Hills, Hyderabad 500034, India

art ic l e i nf o

a b s t r a c t

Article history: Received 4 January 2013 Received in revised form 15 April 2013 Accepted 18 April 2013 Available online 7 May 2013

α4β2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. α4β2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, γ-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which α4β2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective α4β2* neuronal nicotinic acetylcholine receptor ligands are being developed for the treatment of neuropathic and inflammatory pain as they show considerable efficacy in a wide range of preclinical pain models. Agonists/partial agonists of α4β2* neuronal nicotinic acetylcholine receptor show efficacy in animal models of pain and their anti-nociceptive properties are blocked by nicotinic antagonists. Positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of agonists/partial agonists. Accumulating evidences suggest that anti-nociceptive effects of nicotinic acetylcholine receptor ligands may not be mediated solely by α4β2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various α4β2* neuronal nicotinic acetylcholine receptor ligands. & 2013 Elsevier B.V. All rights reserved.

Keywords: α4β2* neuronal nicotinic acetylcholine receptor Neuropathic pain Inflammatory pain

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2. Site and mechanism of action of α4β2* neuronal nicotinic acetylcholine receptor ligands in reducing neuropathic pain and inflammatory pain 23 3. Agonist, partial agonist and allosteric modulators of α4β2* neuronal nicotinic acetylcholine receptor in pain modulation . . . . . . . . . . . . . . . . . 23 4. Is agonism at α4β2* neuronal nicotinic acetylcholine receptor sufficient to produce broad spectrum analgesia? . . . . . . . . . . . . . . . . . . . . . . . . . 25 5. Clinical development of α4β2* neuronal nicotinic acetylcholine receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Press release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

1. Introduction Pain affects the mental and physical well being that significantly interfere with the quality of our daily life. Hence, studying nociceptive mechanisms and identifying potential targets for the treatment of pain have become the top priorities in health organizations as well as pharmaceutical companies (Luo, 2004).

n

Corresponding author. Tel.: +91 40 23541142/23556039; fax: +91 40 23541152. E-mail address: [email protected] (R. Nirogi).

0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.04.021

While opioids and NSAIDS (Non steroidal anti-inflammatory drugs) remain the most commonly prescribed pain medications, these drugs cause side effects which include drowsiness, nausea, respiratory depression, vomiting, constipation, dependence and gastrointestinal disturbances (Woodcock, 2009). Despite strong analgesic activity, some neuropathic pain conditions are resistant to opioid therapy (Ollat and Cesaro, 1995; Mc Cormick and Schreiner, 2001; Smith, 2012). Antidepressant, anticonvulsant and local anaesthetic drugs are being currently used for the treatment of neuropathic pain, but they offer limited therapeutic efficacy (Finnerup et al., 2010).

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The analgesic effects of nicotine have been demonstrated in preclinical and clinical studies. It was shown that nicotine given as nasal spray or transdermal patch has analgesic effects in clinical studies, however patients reported higher levels of nausea and increase in heart rate (Flood and Daniel, 2004; Hong et al., 2008; Yagoubian et al., 2011). The anti-nociceptive effects of nicotine are thought to be mediated through nicotinic acetylcholine receptor and attenuated by the treatment of mecamylamine (brain penetrant nicotinic acetylcholine receptor antagonist) in preclinical studies (Cooley et al., 1990; Iwamoto, 1991; Tripathi et al., 1982). The most widely distributed nicotinic receptor subtype in the brain is α4β2* heteromeric (α-bungarotoxin-insensitive) nicotinic acetylcholine receptor (Hogg et al., 2003; McGehee and Role, 1995). Nicotine acts as an agonist and display higher selectivity towards these receptor (Hogg and Bertrand, 2007). First evidence implicating α4β2* neuronal nicotinic acetylcholine receptor in the pain modulation comes from studies demonstrating that α4- and β2-knockout mice showed reduced anti-nociceptive effect of nicotine (Marubio et al., 1999). The anatomical distribution of α4β2* neuronal nicotinic acetylcholine receptor in the brain and the spinal cord supports a role of these receptor in nociceptive transmission (Gotti et al., 2006; Shi et al., 2010). Activation of presynaptic α4β2* neuronal nicotinic acetylcholine receptor increases the release of multiple neurotransmitters in the brain including acetylcholine, dopamine, γ-amino butyric acid (GABA) and norepinephrine (Jensen et al., 2005; Sher et al., 2004).

2. Site and mechanism of action of α4β2* neuronal nicotinic acetylcholine receptor ligands in reducing neuropathic pain and inflammatory pain Several sites of action have been proposed for the antinociceptive action of α4β2* neuronal nicotinic acetylcholine receptor ligands including spinal and supraspinal sites. α4β2* neuronal nicotinic acetylcholine receptor are present in nucleus raphe magnus (NRM), dorsal raphe (DR), locus coeruleus (LC) (Bitner et al., 1998; Cucchiaro and Commons, 2003; Cucchiaro et al., 2005; Galindo-Charles et al., 2008; Gotti et al., 2006). Many of these areas are thought to play a major role in descending monoaminergic inhibitory pain pathway. Midbrain periaqueductal gray (PAG) is a major component of the descending inhibitory pathway contains α4β2* neuronal nicotinic acetylcholine receptor and mediate GABAergic synaptic transmission (Nakamura and Jang, 2010). Several studies were carried out to find the brain regions involved in the analgesic action of α4β2* neuronal nicotinic acetylcholine receptor ligands. It has been reported that epibatidine's analgesic action is mediated through α4β2* neuronal nicotinic acetylcholine receptor in the NRM (Cucchiaro et al., 2005) and LC regions (Cucchiaro et al., 2006). α4β2* neuronal nicotinic acetylcholine receptor present in the NRM, DR and LC mediate anti-nociceptive effects of ABT-594 (Bitner et al., 1998; Decker et al., 1998a, 1998b) and A-85380 (Bitner et al., 2000; Curzon et al., 1998; Nikkel et al., 1998). In addition to the supraspinal pathways, spinal pathways are also involved in the anti-nociceptive activity of α4β2* ligands. The peripheral site of antinociceptive action of A-85380 was demonstrated by blocking the nociception through infusion of the compound into the injured dorsal root ganglion (Rueter et al., 2003). In the spinal cord, presynayptic activation of α4β2* neuronal nicotinic acetylcholine receptor exerts tonic inhibition on nociceptive transmission (Rashid et al., 2006). It is also important to note that, activation of α4β2* neuronal nicotinic acetylcholine receptor leads to the release of serotonin and norepinephrine in the spinal cord which are primarily involved in the descending inhibitory pathway (Li and Eisenach, 2002; Rueter et al., 2000).

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Moreover, involvement of descending noradrenergic, serotonergic, and muscarinic spinal pathways in the anti-nociceptive effects of systemically administered A-85380 was demonstrated using intrathecal administration of scopolamine, methysergide, MDL 72222 and idazoxan (Rueter et al., 2000). The spinal GABAergic system is also involved in the analgesia mediated via α4β2* neuronal nicotinic acetylcholine receptor. (−) Nicotine-induced analgesia mediated through the α4β2* neuronal nicotinic acetylcholine receptor was blocked by GABAA antagonists, which suggest that, α4β2* neuronal nicotinic acetylcholine receptor are responsible for the enhancement of spinal cholingergic-GABAergic transmission (Genzen and McGehee, 2005; Rashid and Ueda, 2002). This is consistent with the recent finding which demonstrated the role of β2* neuronal nicotinic acetylcholine receptor in controlling GABAA receptor-mediated inhibitory transmission in the spinal cord of knockout mice (Yalcin et al., 2011). Apart from the inhibitory GABAergic neurons, α4β2* neuronal nicotinic acetylcholine receptor are also found in the inhibitory glycinergic neurons of spinal cord (Abdin et al., 2006; Kiyosawa et al., 2001). α4β2* neuronal nicotinic acetylcholine receptor ligands remains the attractive strategy for the management of neuropathic and inflammatory pain. Neuropathic pain is associated with damage to peripheral or spinal nerves or injury to spinal cord. Mechanisms involved in the neuropathic pain include peripheral or central sensitization, loss or hypoactivity of the descending inhibition. α4β2* neuronal nicotinic acetylcholine receptor ligands were evaluated in a variety of neuropathic pain models like partial sciatic nerve ligation (PNL), chronic constriction injury (CCI), spinal nerve ligation (SNL), diabetic and chemotherapy induced neuropathic pain. The anti-inflammatory role of nicotine is well documented, and transcripts for neuronal nicotinic acetylcholine receptor subunits α4 and β2 have been detected in multiple inflammatory cell types (Matsunaga et al., 2001). Hosur et al. (2009) demonstrated that nicotine suppresses the expression of proinflammatory cytokines such as IL-1β and IL-6 through α4β2* neuronal nicotinic acetylcholine receptor using microarray analysis. This finding is in accord with another report from the same group which showed that nicotine attenuates lipopolysaccharide (LPS) induced inflammation through α4β2* neuronal nicotinic acetylcholine receptor and anti-inflammatory effects are mediated via JAK2-STAT3 transduction (Janus Kinase 2-Signal Transducer and Activator of Transcription 3) (Hosur and Loring, 2011). α4β2* neuronal nicotinic acetylcholine receptor ligands showed efficacy in preclinical models of inflammatory pain like formalin induced nociception (FIN), complete Freund's adjuvant (CFA) induced hyperalgesia, knee joint arthritis pain and bladder inflammatory pain. Collectively, all the above findings suggest that α4β2* neuronal nicotinic acetylcholine receptor could be a promising target for the treatment of neuropathic and inflammatory pain. Efficacy of α4β2* neuronal nicotinic acetylcholine receptor ligands across a range of neuropathic and inflammatory pain models has been well established. Results from the various studies with α4β2* neuronal nicotinic acetylcholine receptor ligands are compiled in Table 1.

3. Agonist, partial agonist and allosteric modulators of α4β2* neuronal nicotinic acetylcholine receptor in pain modulation The genesis for pain management through α4β2* neuronal nicotinic acetylcholine receptor initiated after the isolation of epibatidine from the skin of frog Epipedobutes tricolor which is approximately 200-fold more potent than morphine in producing analgesia (Sullivan and Bannon, 1996). Epibatidine is agonist at α4β2* neuronal nicotinic acetylcholine receptor and interacts with

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Table 1 Efficacy of α4β2* neuronal nicotinic acetylcholine receptor ligands in various animal models of pain. Compound

Animal model (Reference no)

Route of administration

Tested doses

Active doses

Ligand type

Reference (no)

Nicotine

Hot plate test(1) Tail flick(2) FIN(3) Hot plate test(4) Tail flick(5)

s.c. s.c. i.p. s.c. i.c.v

0.32–1.6 mg/kg 2 mg/kg 0.25–1 mg/kg 0.125–0.5 mg/kg 25 μg/rat

1.6 mg/kg 2 mg/kg 0.25–1 mg/kg 0.25–0.5 mg/kg 25 μg/rat

Agonist

Boyce et al. (2000) (1) Damaj et al. (1999) (2) Zarrindast et al. (2004) (3) Caggiula et al. (1995) (4) Rao et al. (2004) (5)

Epibatidine

Hot plate test(1) Tail flick(6) CFA(6) PNL(6) FIN(7) Knee joint arthritis(8)

s.c. s.c. s.c. s.c. s.c. Infusion (dorsal horn)

0.001–0.1 mg/kg 0.3–10 mg/kg 0.3–10 mg/kg 0.3–10 mg/kg 2.5–5 mg/kg 0.005–0.5 mg/ml

0.1 mg/kg 3, 10 mg/kg 1,3,10 mg/kg 0.3–10 mg/kg 5 mg/kg 0.005 mg/ml

Agonist

Boyce et al. (2000) (1) Kesingland et al. (2000) (6)

SNL(9) Diabetic neuropathy(9) Hot plate test(1) Tail flick(6) CFA(6) PSNL(6) Thermal pain(10) FIN(10) SNL(10) Chemotherapy induced pain(11), neuropathy(11) Post-operative pain(12) Visceral pain(13)

i.p. i.p. s.c. s.c. s.c. s.c. i.p. i.p. i.p. i.p.

0.03–1 μmol/kg 0.1 and 0.3 μmol/kg 0.001–0.1 mg/kg 10–300 μg/kg 3–100 μg/kg 3–100 μg/kg 0.03–0.3 μmol/kg 0.03–0.3 μmol/kg 0.03–0.3 μmol/kg 0.01–1 μmol/kg

0.1–1 μmol/kg 0.3 μmol/kg 0.1 mg/kg 300 μg/kg 10–100 μg/kg 3–100 μg/kg 0.03–0.3 μmol/kg 0.03–0.3 μmol/kg 0.1, 0.3 μmol/kg 0.03–1 μmol/kg

Agonist

i.p. i.c.v

0.03–0.3 μmol/kg 0.03–0.3 μmol/kg

0.3 μmol/kg 0.1, 0.3 μmol/kg

ABT-894

SNL(14) Chemotherapy induced neuropathy(14)

i.p. i.p.

0.62–19 μmol/kg 0.62–19 μmol/kg

0.62–19 μmol/kg 0.62–19 μmol/kg

Agonist

Rueter et al. (2008) (14)

A-85380

SNL(15)

i.p.

0.125–1 μmol/kg

0.5–1 μmol/kg

Agonist

Rueter et al. (2003) (15)

A-366833

Hot Box(16) FIN(16) SNL(16) Abdominal constriction model(16) CCI(17) PSNL(17) SNL model(17) CFA(17) Diabetic neuropathy(17) Chemotherapy induced neuropathy(17)

i.p. i.p. i.p. i.p. i.p. i.p. i.p. i.p. i.p. i.p.

0.62–19 μmol/kg 1.9–19.0 μmol/kg 1.9–19 μmol/kg 0.019–0.62 μmol/kg 1–6 mg/kg 1–6 mg/kg 1–6 mg/kg 1–6 mg/kg 1–6 mg/kg 1–6 mg/kg

6.2–19 μmol/kg 1.9–19.0 μmol/kg 1.9–19 μmol/kg 0.062–0.62 μmol/kg 3, 6 mg/kg 3, 6 mg/kg 6 mg/kg 3, 6 mg/kg 3, 6 mg/kg 3, 6 mg/kg

Agonist

Ji et al. (2007) (16)

TC-6499

Diabetic neuropathy(18) Chemotherapy induced neuropathy(18)

p.o. p.o.

0.01–1 mg/kg 0.01–1 mg/kg

0.1–1 mg/kg 0.01–1 mg/kg

Agonist

Jordan et al. (2007) (18)

TC-2559

FIN(19) CCI(19)

i.p. i.p.

1–10 mg/kg 0.3–3 mg/kg

3 , 10 mg/kg 1–3 mg/kg

Agonist

Cheng et al. (2011) (19)

RJR 2403

Tail flick(2)

s.c.

12 mg/kg

2 mg/kg

Agonist

Damaj et al. (1999) (2)

SIB 1663

Tail flick(20)

i.c.v

12.5–200 μg/rat

50, 100 μg/rat

Partial agonist

Rao et al. (2004) (20)

Sazitidine

FIN(21)

i.p.

0.125–2 mg/kg

0.5–2 mg/kg

Partial agonist

Cucchiaro et al. (2008) (21)

ABT-594

Cucchiaro et al. (2005) (7) Lawand et al. (1999) (8) Lawand et al. (1999) (8) Bannon et al. (1998b) (9) Boyce et al. (2000) (1) Kesingland et al. (2000) (6)

Decker et al. (1998) (10) Lynch et al. (2005) (11) Gauvin et al. (2003) (12) Joshi et al. (2008) (13)

Nirogi et al. (2011) (17)

FIN—Formalin induced pain, CFA—Complete Freund's adjuvant, SNL—Spinal nerve ligation, CCI—Chronic constriction injury, PSNL—Partial sciatic nerve ligation.

several of the other subtypes including α7 and α4β2* neuronal nicotinic acetylcholine receptor (Sullivan et al., 1994). The antinociceptive effect of epibatidine was blocked with pretreatment of nicotinic acetylcholine receptor antagonist mecamylamine but not by opioid receptor antagonist naloxone (Bonhaus et al., 1995; Qian et al., 1993). Although epibatidine showed potent analgesic activity, its nonselective activity at peripheral neuromuscular and ganglionic nicotinic acetylcholine receptor leads to cardiovascular, central nervous system (CNS) toxicity which rendered this compound unsuitable for further development (Sullivan and Bannon, 1996). ABT-594, a selective agonist at α4β2* neuronal nicotinic acetylcholine receptor against α7 and neuromuscular α1β1 neuronal nicotinic acetylcholine receptor (Donnelly-Roberts et al., 1998)

from Abbott laboratories showed dose dependent analgesic activity in preclinical models of pain. Like epibatidine, the antinociceptive effects of ABT-594 were attenuated by pretreatment with the neuronal nicotinic acetylcholine receptor antagonists such as mecamylamine and chlorisondamine, but not with the pretreatment of opioid receptor antagonist, naltrexone (Bannon et al., 1998a). The findings from the pharmacological blockade studies using nicotinic antagonists elucidate that activation/agonism of α4β2* neuronal nicotinic acetylcholine receptor is essential for the anti-nociceptive activity of these compounds (Bannon et al., 1998a; Bonhaus et al., 1995; also see Decker and Meyer, 1999). Other than epibatidine and ABT-594, range of α4β2* neuronal nicotinic acetylcholine receptor agonists like A-85380

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(Curzon et al., 1998; Rueter et al., 2000), A-366833 (Ji et al., 2007), RJR-2403 (metanicotine) (Damaj et al., 1999), ABT-894 (Zhang et al., 2012) and TC-6499 (Jordan et al.,2007) demonstrated excellent potency and efficacy in rodent models of pain (Table 1). The analgesic activity was blocked by neuronal nicotinic acetylcholine receptor antagonists indicating that the observed effect is mediated through nicotinic acetylcholine receptor. Experimental evidences suggest that tolerance develops to the analgesic effects of nicotine (Cepeda-Benito et al., 1998, 2000). The rapid development of tolerance to the analgesic activity of nicotine is due to desensitization of neuronal nicotinic acetylcholine receptor (McCallum et al., 1999; Turan et al., 2008) and chronic nicotine exposure desensitizes α4β2* neuronal nicotinic acetylcholine receptor (Buisson and Bertrand, 2001; Lo'pez-Herna'ndez et al., 2004). Tolerance to the anti-nociceptive effect developed upon chronic treatment with (−) epibatidine, but not with the (+) epibatidine (Damaj and Martin, 1996). However, selective α4β2*neuronal nicotinic acetylcholine receptor agonists TC-6499 and ABT-894 showed anti-nociceptive activity upon acute as well as repeated administration in rodent models of neuropathic pain (Jordan et al., 2007; Rueter et al., 2008) and this was further supported by the positive phase 2 clinical trial results of ABT-594 after 7 weeks treatment for neuropathic pain (Rowbotham et al., 2009). Abuse and addiction liability may hinder the development of α4β2* neuronal nicotinic acetylcholine receptor agonists for pain therapy. Surprisingly repeated administration of ABT-594 did not show opioid like withdrawal effects or place preference in conditioned place preference task (Bannon et al., 1998a). Despite adequate proof of concept for the involvement of α4β2* neuronal nicotinic acetylcholine receptor in addiction, role of α6 and α7 containing nicotinic receptor in the nicotine induced reinforcement cannot be ruled out (Besson et al., 2012; Exley et al., 2008; Gotti et al., 2010; Yang et al., 2009). All the above suggest that α4β2* neuronal nicotinic acetylcholine receptor agonists may provide a useful approach for the treatment of pain with an effective and better safety profile than nicotine as such. Numerous non selective and selective partial agonists of α4β2* neuronal nicotinic acetylcholine receptor showed efficacy in preclinical models of pain. Varenicline, a partial agonist of α4β2* neuronal nicotinic acetylcholine receptor and agonist of α7 neuronal nicotinic acetylcholine receptor dose dependently reduced formalin induced flinches in rats (Gao et al., 2010). TC-2559, a selective partial agonist showed anti-nociceptive effects in FIN and CCI models via α4β2* neuronal nicotinic acetylcholine receptor as the selective α4β2* neuronal nicotinic acetylcholine receptor antagonist dihydro-βerythrodine (DHβE) blocked the analgesic effect (Cheng et al., 2011). A similar observation was made upon combined administration of sazetidine with noncompetitive nicotinic antagonist mecamylamine (Cucchiaro et al., 2008; Zwart et al., 2008). Although partial agonists produced substantial anti-nociceptive activity, it was demonstrated that activation or agonism of α4β2* neuronal nicotinic acetylcholine receptor play an essential role in analgesic activity of nicotinic ligands using non selective and selective α4β2* neuronal nicotinic acetylcholine receptor antagonists. The lack of anti-nociceptive activity observed with ABT-089 (Decker, 2004), TC-1734 (Gao et al., 2010) and A-424274 (Lee et al., 2011) raises concern about the role of selective α4β2* neuronal nicotinic acetylcholine receptor partial agonists in pain modulation. ABT-089 and TC-1734 showed procognitive activity (Gatto et al., 2004; Rueter et al., 2004). Recently, it was suggested that full agonism is required at α4β2* neuronal nicotinic acetylcholine receptor to observe the analgesic activity in preclinical models of pain (Lee et al., 2011). Positive allosteric modulators are defined as ligands that increase potency by acting at a site different from the orthosteric site (Bertrand and Gopalakrishnan, 2007). Selective positive allosteric modulators increase potency of the α4β2* neuronal nicotinic acetylcholine receptor ligands, but it may or may not change the

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maximal efficacy of the agonist (Pandya and Yakel, 2011). NS9283, a positive allosteric modulator of α4β2* neuronal nicotinic acetylcholine receptor increased the therapeutic window by reducing the side effect profile of non selective agonist ABT-594 in animal models of neuropathic pain. Furthermore, combination of A-424274, a selective α4β2* neuronal nicotinic acetylcholine receptor partial agonist (o5% intrinsic activity) with NS9283 produced analgesic activity in SNL (Lee et al., 2011). Since, it is complex to develop a potent selective full agonist with favorable side effect profile, positive allosteric modulators of α4β2* neuronal nicotinic acetylcholine receptor may unravel this issue.

4. Is agonism at α4β2* neuronal nicotinic acetylcholine receptor sufficient to produce broad spectrum analgesia? Nicotine is prototype agonist that shows a broad spectrum antinociceptive and anti-inflammatory action. α7 nicotinic agonists have shown analgesic like activity in some of pain models like tail flick (Damaj et al., 2000) and post operative pain models (Rowley et al., 2008). Involvement of α5 containing neuronal nicotinic acetylcholine receptor in pain modulation was shown by studies using knock down of α5 subunit in the rat with spinal nerve ligation (Vincler and Eisenach, 2005). This was further supported by the fact that α5 transcripts and expressed subunits are present in the dorsal root ganglion as well as spinal interneurons (Khan et al., 2003) and various agonists may have different sensitivity towards α4β2α5* neuronal nicotinic acetylcholine receptor (Gao et al., 2010). Gao et al. (2010) also suggested that agonism of α4β2* neuronal nicotinic acetylcholine receptor is necessary but may not be adequate to produce analgesia. The authors of this study also found that the selective α4β2* neuronal nicotinic acetylcholine receptor agonist TC-1734 and a novel α4β2* neuronal nicotinic acetylcholine receptor selective potentiator did not produce anti-nociceptive activity in the formalin test and CFA induced inflammatory pain model. Zhang et al. (2012) showed a correlation using ABT-894 and Sazetidine-A, which showed anti-nociceptive activity in formalin test and with the set of compounds which showed a range of activities at human (α4β2)2β2 (HS-α4β2), (α4β2)2 α5 (α4β2α5) and (α4β2)2 α4 (LS-α4β2) receptor, stating that α4β2α5 neuronal nicotinic acetylcholine receptor played prominent role in analgesic activity of the compounds in formalin test. α9α10 neuronal nicotinic acetylcholine receptor participation in neuropathic pain was demonstrated in models like PNL and CCI of sciatic nerve (Satkunanathan et al., 2005). Takeda et al. (2003) showed that nicotine mediated inhibitory synaptic activity was modulated by a non-α4β2*, non-α7 subtype possibly α3β4 neuronal nicotinic acetylcholine receptor or a new nicotinic acetylcholine receptor type. In α4 hypersensitive knock in mice, supraspinal responses (hot plate assay) of nicotine were mediated by α4β2* neuronal nicotinic acetylcholine receptor while spinal responses (tail flick assay) of nicotine was modulated by α4β2* neuronal nicotinic acetylcholine receptor and at least one other nicotinic acetylcholine receptor subtype (Damaj et al., 2007). Spinal α3β2 nicotinic acetylcholine receptor tonically inhibits the transmission of nociceptive mechanical stimuli by facilitating the release of inhibitory neurotransmitters (Young et al., 2008). Thus accumulating evidences suggest that anti-nociceptive effects of neural nicotinic receptor ligands may not be mediated solely by α4β2* neuronal nicotinic acetylcholine receptor.

5. Clinical development of α4β2* neuronal nicotinic acetylcholine receptor agonists α4β2* neuronal nicotinic acetylcholine receptor agonists are a recent development in the study of potential treatment of pain,

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and they show a broad spectrum anti-nociceptive activity in preclinical models of both inflammatory and neuropathic pain. Proof of concept for α4β2* neuronal nicotinic acetylcholine receptor agonists as a new class of compounds for the treatment of neuropathic pain was demonstrated with ABT-594. However, high incidence of adverse effects like nausea, dizziness and emesis were observed with this molecule in phase 2 clinical trials (Rowbotham et al., 2009). Later it was observed that side effects with ABT-594 were mediated through ganglionic α3β4 neuronal nicotinic acetylcholine receptor (Zhu et al., 2011). Recently Lee et al. (2011) showed that NS9283, a α4β2* neuronal nicotinic acetylcholine receptor positive allosteric modulator selectively enhanced the analgesic activity of ABT-594 without activating the brainstem emetic center at the examined doses. However, the concept of combining a positive allosteric modulator with α4β2* neuronal nicotinic acetylcholine receptor agonists to improve the therapeutic window remains to be demonstrated clinically. ABT-894, a selective α4β2* neuronal nicotinic acetylcholine receptor agonist with an improved therapeutic window for gastrointestinal and CNS side effects (Rueter et al., 2008) was discovered under drug discovery collaboration between Neurosearch and Abbott. The preclinical data have demonstrated the efficacy of ABT-894 in multiple models of neuropathic pain (Rueter et al., 2008). ABT-894 was well tolerated, but failed to alleviate pain in two phase 2 studies of diabetic neuropathic pain at the tested doses of 1, 2, 4 and 6 mg BID (Rowbotham et al., 2012). TC-2696, α4β2* neuronal nicotinic acetylcholine receptor agonist from Targacept was well tolerated in phase 2 trial of postoperative dental pain, but failed to meet the primary end points (Targacept press release—December, 03, 2007). The development of another α4β2* neuronal nicotinic acetylcholine receptor agonist (TC-6499) was discontinued due to the lack of sufficient therapeutic margin in phase 1 multiple ascending dose. Targacept stated that a compound with concurrent activity at multiple nicotinic acetylcholine receptor subtypes may have increased potency (Targacept press release—March 11, 2009). Recently targacept completed a proof of concept study for TC-6499 in the treatment of constipation predominant irritable bowel syndrome (Clinical trials.gov—NCT01149200), but the outcome is not known. α4β2* neuronal nicotinic acetylcholine receptor ligands (clinical candidates) have a wide therapeutic avenue ranging from pain to cognitive disorders. α4β2* neuronal nicotinic acetylcholine receptor full agonist ABT-418, tested for smoking cessation showed positive results in phase-2 (Arneric et al., 2007). Partial agonist like CP-601927 and CP-601932 were well tolerated and showed positive effects, but their efficacy was not better than Varenicline (Chatterjee et al., 2011; Mineur et al., 2011; Hurst et al., 2013). ABT894 (Bain et al., 2013), ABT-089 (Apostol et al., 2012), ispronicline (Locke et al., 2010) showed positive effects in adults with attention deficit-hyperactivity disorder (ADHD). The positive effect in ADHD patients with α4β2* neuronal nicotinic acetylcholine receptor ligands may be due to the special character of β2 subunit which elicited nicotinic properties like potentiation of dopamine (Smith et al., 2007) and release of acetylcholine (Ueno et al., 2002). These features were not associated with other nicotinic acetylcholine receptors like α3β4 and α7 (Smith et al., 2007; Ueno et al., 2002). The α4β2* neuronal nicotinic acetylcholine receptor partial agonists ispronicline (TC-1734, AZD3480) tested for cognitive performance showed favorable Phase-1 safety and pharmacokinetic profile (Gatto et al., 2004). Frölich et al. (2011) reported that ispronicline failed to meet its primary endpoint of Assessment Scale-Cognitive Subscale (ADAS-cog) score in Alzheimer's disease (AD) patients, interestingly significant improvement in measures of attention and memory was observed in elderly patients with age-associated memory deficit (Dunbar et al., 2010). ABT-418, a full agonist (Arneric et al., 1994) showed significant improvement in

verbal learning task in six moderate AD patients (Potter et al., 1999), however further development was halted for AD due to lack of efficacy in a larger AD trial (Arneric et al., 2007). α4β2* neuronal nicotinic acetylcholine receptor partial agonists like Varenicline when tested on smokers with stable antidepressant condition showed improvement in Quick Inventory of Depressive Symptomatology Scale-Self-Report (QIDS-SR) and Clinical Global Impressions-Severity Scale (CGI-S) (Philip et al., 2009). However CP-601927 failed to meet its end points in depressed patients (Hurst et al., 2013).

6. Conclusion α4β2* neuronal nicotinic acetylcholine receptor regulates different process of pain pathways by inhibiting the incoming pain signals and modulate the pain perception. α4β2* neuronal nicotinic acetylcholine receptor ligands have been shown to be effective in a number of animal models of neuropathic and inflammatory pain. The clinical trials of α4β2* neuronal nicotinic acetylcholine receptor agonists showed mixed results and raise the possibility of additional neural nicotinic receptor involved in the control of pain. The side effect profile of α4β2* neuronal nicotinic acetylcholine receptor agonists was better than opioids in clinical trails (without constipation, sedation, respiratory depression and pruritus like effects) (Rowbotham et al., 2009), similarly premature discontinuation rates due to adverse events was lesser with selective α4β2* neuronal nicotinic acetylcholine receptor agonist when compared to Duloxetine (Rowbotham et al., 2012). Thus a better efficacy and side effect profile are the positive aspects of α4β2* neuronal nicotinic acetylcholine receptor agonists compared to the currently used analgesics. Challenge for the development of novel α4β2* neuronal nicotinic acetylcholine receptor ligands for the treatment of pain lies in translation of preclinical efficacy into the clinic.

Declaration of interest All authors are current employees of Suven Life Sciences Ltd.

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Press release Targacept Announces Results of Phase II Study of TC-2696 in Postoperative Dental Pain. Targacept Press Release, December 03, 2007. 〈http://www.targacept.com/ wt/page/pr_1196665010〉 (3.01.12). Targacept Provides Update on TC-6499 and Pain Program in GlaxoSmithKline alliance. Targacept Press Release, March 11, 2009. 〈http://www.targacept.com/ wt/page/pr_1236700125〉 (3.01.12).