Chapter 1. Current and emerging opportunities for the treatment of neuropathic pain

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Editor: David W. Robertson, Pfizer Global Research Ann Arbor, MI 48105 Chapter

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John A. Butera and Michael R. Brandt Wyeth Research CN 8000, Princeton, NJ 08543-8000 introduction - Neuropathic pain is characterized by abnormal pain sensations, including spontaneous pain, hyperalgesia (i.e., increased sensitivity to a noxious stimulus) and allodynia (i.e., increased sensitivity to a non-noxious stimulus) that typically lack an apparent physiologic function. In general, neuropathic pain is chronic and is refractory to current pharmacotherapies. Numerous recent advancements have contributed to a better, though still not complete understanding of the physiology and neurobiology of pain. It is now appreciated that many distinct mechanisms contribute to the development and maintenance of neuropathic pain. Some of these mechanisms have strong preclinical and clinical rationale as small molecule targets for neuropathic pain conditions. Compounds selective for these targets could potentially offer improved pain relief with fewer adverse effects compared to currently available treatments. The goal of the current review is to highlight small molecules with potential for treating neuropathic pain. N-METHYL-D-ASPARTATE

RECEPTOR

(NMDAR)

MODULATORS

Numerous studies have demonstrated a role for excitatory amino acids in the development and maintenance of chronic neuropathic pain (1,2). Increased afferent input can lead to central sensitization via release of glutamate within the spinal cord (3,4). A significant medicinal chemistry effort has identified numerous molecules that either inhibit the release or block the effects of glutamate. The NMDAR is a ligand-gated ion channel containing numerous regulatory sites including glutamate, glycine, polyamine, Mg” and PCP binding sites, all of which modulate channel activity. In addition to multiple regulatory sites, NMDARs are hetero-oligomers consisting of NRI subunits, of which there are eight identified splice variants, plus a combination of NR2A-D subunits. Importantly, the pharmacology and ion gating properties of NMDAR channels are substantially altered with different combinations of NRI and NR2 subunits (5). Recently NR3A and NR3B subunits have been identified, which confer distinct channel activity when combined with NRI (6). Moreover, NMDAR subunits are differentially distributed among pain pathways in the central nervous system suggesting that specific subunits might preferentially modulate pain signaling (7). These aspects of NMDARs have provided numerous approaches for small molecule design (5). NMDAR Glutamate Site Antaaonists - Preclinical and clinical studies demonstrate that competitive glutamate antagonists reverse hypersensitivity associated with In general, most competitive glutamate site neuropathic pain states (8,9). antagonists contain phosphono amino acids separated from carboxyl groups by four or six atoms. One such example, selfotel (cis-4-(phosphono-methyl)-2-piperidine carboxylic acid), reversed mechanical hypersensitivity in a spinal cord ischemia model; however, these effects occurred at doses that also produced motor impairments. Although some glutamate antagonists (e.g., selfotel) were advanced ANNUAL REPORTS IN MEDICINAL CHEMISTRY-38 ISSN: 0065.7743

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to clinical studies for indications other than pain (i.e., stroke), adverse effects caused the discontinuation of these programs. The failure of glutamate antagonists might be due to the highly conserved glutamate-binding pocket on NR2 subunits and subsequent difficulty obtaining selectivity among NR2 subunits (10). However, studies indicate specificity among subtypes occurs with some molecules. For example, D-(-)-(E)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (CPPene) and selfotel exhibit 20 to 40-fold subunit selectivity for NRlINR2A or NR2B over NRlINR2C or NR2D (11). However, little separation is typically observed between NRlINR2A over NRl/NR2B, which might be important for obtaining improved adverse effect profiles. More recently, conantokin G, a peptide venom from the marine cone snail Conus geographus, was characterized as a NRlINR2B selective glutamate antagonist (12). Characterization of the interaction of this peptide with specific residues of the NR2B subunit might lead to novel competitive glutamate antagonists (13). NMDAR Glvcine Site Antaqonists - NMDARs require glutamate, as well as the coagonist glycine, for channel activation. Thus, an alternative approach for modulating channel activity has been to develop selective glycine site antagonists (14). Although many glycine antagonists apparently lack NR2 subunit selectivity, which might be related to the glycine-binding site residing on the widely distributed NRI subunit, the azidoI probe 1 (CGP51594) has been described as a glycine antagonist having IO-fold higher selectivity for cr&&r% HI&c, NRl/NR2B subunits HN than for NRlINR2A H i 2 subunits (1% Activity of 1 for blocking pain has not been published, however GV-196771A (2) reversed chronic constriction injury (Ccl) of the sciatic nerve-induced thermal and tactile hypersensitivity after p.o. doses of I-IO mglkg (16). In clinical trials, compound 2 significantly reduced static and dynamic allodynia associated with neuropathic pain yet did not reduce evoked pain intensity or produce pain relief (17). The reason for its lack of efficacy in humans is unclear. NMDAR Channel Blockers - Clinically available NMDAR antagonists bind within the channel itself and block the flow of ions in a use-dependent manner. Ketamine is a dissociative anesthetic that reverses hypersensitivity in preclinical and clinical neuropathic pain states (8,9). However, the narrow separation between efficacy and adverse effects has hampered the utility of ketamine for the treatment of neuropathic pain. Memantine is a low affinity channel blocker that s’ displaces [3H]-MK-801 binding from rat membranes with a K, of approximately 1 pM (18). Memantine was --s effective in reversing Ccl-induced thermal and SNLinduced tactile hypersensitivity (18). Differences in the adverse effect profile of these non-competitive antagonists are attributed to the affinity and voltage dependency for which they bind within the channel 3 (18). CNS 5161 (3J is another channel blocker that has a Kr of 1.8 nM in its ability to displace t3H]-MK-801 binding from rat membranes (19). Although preclinical data of 3 are not published, its mechanism of action suggests it would be efficacious in neuropathic pain models.

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NMDAR Polvamine-like Antaaonists - Based on localization, biochemical and pharmacological data, it has been hypothesized that NRPB subunits preferentially mediate pain transmission. Traxoprodil (CP-101606,g) has a binding affinity (&,) of IO nM and dose-dependently reversed z L5/L6 sciatic nerve ligation (SNL)-induced w,,. = N mechanical hypersensitivity (3 - 10 mg/kg; i.p.). A lo-fold higher dose did not produce disturbances in motor :I /“; coordination (20,21). More recently synthesized benzamide derivatives have 6%OH -4 greater than 20,000-fold selectivity for ‘\ recombinant NRl/NR2B receptors than for OH NRl/NR2A receptors (22). Related Ho , piperazine 5 had good oral bioavailability xl 1’ c@ as indicated by EDso values of 5.5 to 16 O-N 2 mg/kg for reversing carrageenan-induced hypersensitivity (23). These findings suggest that NR2B selective antagonists might have clinical utility in treating neuropathic pain with reduced adverse effects compared to non-selective antagonists. OTHER GLUTAMATE

MECHANISMS

Metabotrophic Glutamate Receptor (mGluR1 Modulators - Metabotropic glutamate receptors consist of eight different subunits of G protein coupled receptors that are classified into three groups [group I receptors (mGluR IS), group II (mGluR 2,3) and group III (mGluR 4,6,7,8)] based on sequence homology, coupling to intracellular messengers and pharmacologic profile (24,25). Recently, the mGluR5 selective compound $ (MPEP) was identified and shown to reverse mechanical hypersensitivity in the Freund’s complete adjuvant (FCA) inflammatory pain model without modifying the magnitude of edema at p.o. doses between 10 and 30 mg/kg (26). However, a higher dose of 100 mglkg p.o. failed to reduce mechanical / \ hypersensitivity in a neuropathic pain model (26). While 04 these data suggest the potential for Group 1 antagonists s in inflammatory pain, their weak effects for reversing established allodynia in neuropathic pain models suggest that they might have limited potential as clinical pharmacotherapies (27,28). Recently described mGluR1 and mGluR2 ligands might provide additional insight into their clinical utility (25). NAALADase Inhibitors - Glutamate carboxypeptidase II (GCP II; also termed Nacetylated-a-linked-acidic dipeptidase or NAALADase) is a membrane bound enzyme that hydrolyses N-acetyl-L-aspartyl-L-glutamate (NAAG) to form N-acetylaspartate and glutamate (29). In this regard, GCP II terminates the agonist activity of NAAG at mGluR3 and liberates glutamate. Importantly, the release of NAAG and hydrolysis to glutamate appears to increase under conditions of neuronal excitability observed in some neurological diseases. Selective GCP II inhibitors, such as 2PMPA (2, have been shown to have antiallodynic and antihyperalgesic effects in a number of pain models following Lt. or i.v. administration (30). Another GCPII

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inhibitor, GPI-5232 (6J partially blocked the development of thermal hypersensitivity following daily dosing i.p. in a genetic model of insulin-dependent Type I diabetes (31). Other compounds such as thiol 9 were recently synthesized and inhibit GCP II activity (32,33). OTHER

ION CHANNEL

MECHANISMS

Ion channels, a family of diverse, membrane-bound proteins, provide a plethora of potential targets for design of novel pharmacotherapeutics. Modulation of these proteins by endogenous ligands or transmembrane voltage plays a predominant role in regulating cellular processes that govern excitability. The proven clinical efficacy of ion channel modulators coupled with recent studies demonstrating altered expression of channels in neuropathic pain models, has fueled efforts to design channel-based therapeutics for alleviating neuropathic pain. N-Type Calcium Channel Modulators - Voltage-gated calcium channels (VGCCs) modulate excitability of nociceptive sensory neurons in the dorsal horn of the spinal cord, and appear to be involved in the development and maintenance of neuropathic pain (34,35). VGCCs are classified into three major categories based upon their electrophysiologic and pharmacologic properties: high voltage-activated (L-, N-, P-, and Q-types), intermediate voltage-activated (R-type) and low voltage-activated (Ttype) (36). N-type VGCCs are expressed mainly on dendrites and pre-synaptic terminals, suggesting a role for these channels in neuropathic pain. Consistent with this idea, knockout of the N-type Ca”2.2 gene in mice decreased the magnitude of inflammatory and neuropathic pain behaviors (37). Ziconotide (SNX-11 I), an amino acid w-conotoxin peptide, is a selective N-type VGCC blocker with preclinical and clinical effects (38). Related peptide toxins isolated from Conus venoms have recently been reported. For example, CNVIIA, a congener of ziconotide, binds selectively with a Kd of 36.3 pM (39). Another amino acid derivative (AM336), isolated from Conus cactus, evoked a dose-dependent antinociception (E&O = 0.11 nmol) after i.t. administration in the rat hind paw model (40). Although its efficacy was comparable to SNX-1 11, AM336 did not exhibit a biphasic dose-response curve like SNX-1 11; most likely due to its enhanced selectivity for the N-type VGCC.

Two recently reported non-peptidic N-type VGCC blockers (IJ and II) possessed antinociceptive effects in pain models. Compound ‘0 had anti-writhing effects with an ED50 = 6 mglkg (i.t.) in rats. Compound 11 (I&O = 1.5 uM in IMR32 assay) was efficacious in the anti-writhing (ED50 = 4.5 mglkg, i.v.), SNL (ED50 = 23 pg, it.), and formalin (EDso = 16 mg/kg, i.v.) pain models (41). However, both compounds also posses modest Na’ channel blocking properties (42). Gabapentin (J.2) represents another class of VGCC modulators, although the mechanism of action is not fully understood. It appears to bind to a216 auxiliary subunits of VGCCs, thus down-regulating neurotransmitter release, an effect that might be related to its clinical utility in neuropathic pain states (43). More recently, pregabalin, ((S)-3-aminomethyl-5-methyl-hexanoic acid) a related a2/6 -selective binder, has shown efficacy for various conditions associated with pain, seizures, and anxiety (44).

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Sodium Channel Modulators - Blockers of voltage-gated Na’ channels (VGSC) have analgesic and anesthetic properties caused by inhibiting the initiation and propagation of action-potentials (35). Most inhibitors of VGSCs show a strong voltage-dependent block, meaning that they inhibit high-frequency repetitive activity without altering normal propagation of action potentials (45). Many clinically used anticonvulsants (e.g., carbamazepine) that block VGSC also have utility for treating neuropathic pain (46). Although these compounds alleviate pain symptoms, they are not widely used due to limited separation between efficacy and adverse effects, likely related to their lack of selectivity among VGSC subtypes. Consequently, synthesis efforts have focused on identifying subtypeselective VGSC blockers. Multiple VGSC subtypes are expressed in DRG neurons including rapidly inactivating, TTXI ; c’ sensitive (TTX-S), and slowly inactivating, TTX-resistant (TTXCl R; Navl.8 and Navl.9) channels (47). Expression of TTX-R channels is restricted predominately to sensory neurons (48). NH2 Antisense oligodeoxynucleotide knockdown of the expression F 3 of Navl .8 reversed SNL-induced allodynia and hyperalgesia NI ’ N (49). Navl .9 has recently been implicated in hyperexcitability Although highly selective TTX-R after nerve injury (50). NH2 compounds have not been reported, BW 403OW92 (13) shows 13 slight selectivity for this subtype of NaCh (51). Several recent

Y

patent applications pain models (52).

have disclosed VGSC blockers that were active in neuropathic However, selectivity for other channels was not disclosed (53).

Potassium Channel Modulators - Voltage gated K’ channels play an important role in conditions of aberrant or excessive excitability, such as epilepsy and neuropathic pain. Activation of these channels results in hyperpolarization of the cell membrane The role for K’ channel and subsequent decrease in neuronal excitability. modulators for treating CNS disorders has been recently reviewed in this series (54). KCNQ channels are a family of channels containing at least five K’ channel genes that have been linked to benign familial neonatal convulsions in humans (55). These channels regulate the “M-current”, a K’ current that is inhibited by muscarine thereby increasing neuronal excitability. The KCNQz/KCNQz heteromultimeric channel is expressed predominately in neurons, whereas KCNQZIKNCQJKNCQ~ channels are found in other tissues. Retigabine (14) is a non-selective KCNQ channel opener that dose-dependently inhibited pain behaviors in models of hyperalgesia and neuropathic pain. A dose of 10 mglkg of 14 was comparable to the effect caused by 60 mglkg of oral gabapentin (56). Compounds 15-g represent a novel series of cinnamide-based KCNQ openers, which significantly reversed SNL-induced hypersensitivity at i.v. doses between 3 and 10 mg/kg (57).

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Compounds in a series of pyridyl-benzamides (19) disclosed as selective KCNCWKCNQ3 openers were reported to be effective at prolonging the latency to lick in the rat hind paw model at p.o. doses between 10 and 100 mglkg, although specific data for compounds were not revealed (58). Vanilloid Receptor Modulators - The vanilloid receptor (VRI) is a member of the transient receptor potential (TRP) family of non-selective cation channels. Capsaicin (a), a natural product derived from hot peppers, acts as an agonist at vanilloid receptors (TRPVRI) located on primary afferent nociceptors (59). In addition to being sensitive to 29, TRPVRI is sensitive to protons and heat thus triggering a robust Ca2’ influx and subsequent depolarization. Prolonged activation can produce desensitization and a subsequent decrease in activity of nociceptor fibers. Thus, topical application of 20 has been used to treat pain, skin itch, and psoriasis, as well as other systemic diseases (60). Although specific ligand-binding domains for 20 have not been published and the endogenous ligands have not been definitively identified, recent studies demonstrate that the endogenous cannabinoid ligand anandamide (21) has agonist effects at TRPVRI receptors (61). Numerous related fatty-acid analogs of 2l- which also have modulatory effects on TRPVRI have recently been described (62). Resiniferatoxin (22) represents yet another, structurally distinct TRPVRI agonist, which has been studied cli;ically (59).

The physiology and pharmacology of TRPVRs suggest that both agonists and antagonists might be useful for treating painful conditions. Peripheral TRPVRI s are expressed primarily on unmyelinated C-fibers; however, reported increased expression of TRPVRI on A-fibers following nerve injury suggests a greater role for these receptors for the modulation of neuropathic pain (63). Studies support the view that TRPVRI antagonists modulate sensitization under pathophysiologic conditions of noxious stimuli (noxious heat and proton activation), but not under normal physiologic conditions (64). For example, capsazepine (23) has been shown to inhibit capsaicin-mediated nocifensive behaviors in rodents (65). Although early studies with e in rat neuropathic pain models suggested limited activity, more recent studies In guinea pig neuropathic pain models indicate greater activity of a (64,66). Numerous series of very closely related urea derivatives have recently been reported as TRPVRI antagonists possessing activity in rodent pain models. Compounds g and 25 represent examples in a series of thioureas that reportedly decreased wnthing by greater than 90% at i.p. doses between 3 and 10 mglkg in the mouse writhing test (67). The pyrido-pyrimidinone compound 3 (ICSO = 65 nM) dosedependently reduced mechanical hyperalgesia after p.o. doses between 0.3 and 30 mglkg (68). Finally, a series of 2-pyridinyl-piperazine derived ureas and ethylene-diamine-derived ureas, illustrated by structures g and 28, respectively, were claimed as potent TRPVRl antagonists (69,70).

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, R2=NHS02CH3

P2X Receptor Antaqonists - P2X receptors are a family of ATP-gated non-selective ion channels of which seven P2X subunits (P2X1-,) have been cloned (71). ATP is the endogenous ligand and produces intense pain when injected intradermally (72). Adenine nucleotide derivatives such as oxidized ATP and TNP-ATP have been reported to possess some P2X sub-type specificity and to produce antinociceptive effects in animal pain models (73,74). Although non-selective, P2 receptor antagonists such as suramin and PPADS were shown to produce antinociceptive responses in neuropathic pain models (71,72,75). The structurally novel, nonnucleotide P2x3- and P2Xzn-antagonist (Ki = 22-92 nM) A-317491 (29) was reported to reverse CCIinduced mechanical and thermal hypersensitivity with EDso values between 10 and 15 Fg/kg s.c (76). The effects were stereospecific, as the corresponding R-enantiomer (A-317344) was inactive. Nicotine Receotor Modulators - Activation of neuronal nicotinic acetylcholine receptors (nACHR) has been associated with analgesic effects in neuropathic pain models (77). The a462-selective nACHR agonist ABT-594 130) had antinociceptive effects in animal pain models with a reduced side-effect profile compared to nicotine (35). Pyridinyl derivative TC-2403 (3l) represents another potent a462-selective

nACHR agonist with potential for a better toxicity profile (78). Recent studies suggest that the a7 nACHR also might modulate pain transmission in rodent models PNU-282987 /32) represents a new quinuclidine-derived a7 nACHR (7% antagonist with a reported binding Ki of 26 nM, although no data were reported on its effects in pain models (80). NON-ION

CHANNEL

MECHANISMS

Due to the overwhelming number of emerging neuropathic pain targets, it became necessary to focus and restrict the current review primarily to ion-channel Other targets, some equally compelling as those classes of therapeutics. highlighted above, are also emerging. Recent advances in the area of G-protein

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coupled receptors (GPCRs) offer additional strategies for the design of effective agents. Galanin, muscarinic, prostanoid, adenosine, cannabinoid, opioid, neuropeptide Y, cholecystokinin, neurokinin, bradykinin, and calcitonin gene-related peptide receptors have been studied as neuropathic pain targets with varying degrees of success (81-91). Neurotrophins, a family of growth factors important for differentiation, growth and survival of neurons, have been shown to be neuroprotective in damaged sensory neurons and as such, might be attractive targets for the treatment of neuropathic pain (92). Studies have demonstrated that serotonin has antinociceptive effects under some conditions in normal animals and anti-allodyniclanti-hyperalgesic effects in some models of neuropathic pain (93-94). Together, these studies support a substantial role of GPCRs and intracellular signaling proteins in conditions of neuropathic pain. Concludina Remarks - Neuropathic pain affects over 26 million patients worldwide, resulting in over $3 billion per year spent on drug therapies; most of which were developed for treating other conditions. Current approaches to treat refractory neuropathic pain are often minimally effective or limited in utility due to nonspecificity at the molecular level, thereby causing serious adverse effects and reduced patient compliance. The ever increasing targets and approaches reviewed in this chapter are a result of an unprecedented increase in the understanding of the underlying pharmacology, physiology, and etiology of pain mechanisms and represent the current and future approaches in neuropathic pain management. There is still a substantial need for better-designed clinical studies and well-defined models of pain to more fully evaluate the potential of these emerging pharmaceuticals in terms of their long-term efficacy and potential side effects. As additional breakthroughs in pain biology evolve, we can look forward to a plethora of novel, more effective approaches for neuropathic pain management. References 1.

2. 3. 4. 5. 6. 7.

a. 9.

10. 11. 12. 13. 14. 15. 16. 17.

K.J. Carpenter and A.H. Dickenson, Curr. Opin. Pharmacol., ?_,57 (2001). B.A. Chizh, Amino Acids, a, 169 (2002). D.L. Somers and F.R. Clemente, Neurosci. Lett., 323, 171 (2002). P.K. Zahn, K.A. Sluka and T.J. Brennan, Pain, l&I, 65 (2002). T. Priestley in “NMDA antagonists as potential analgesic drugs,” D.J.S. Sirinathsinghji, R.G. Hill, Ed., Birkhauser Varlag, Boston, 2002, p.5. J.E. Chatterton, M. Awobuluyi, L.S. Premkumar, H. Takahashi, M. Talantova, Y. Shin, J.K. Cui, S.C. Tu, A.S.K. Kevin, N. Nakanishi, G. Tong, S.A. Lipton and D.X. Zhang, Nature, 415,793 (2002). M. Rigby, R.P. Heavens, D. Smith, R. O’Donnell, R.G. Hill and D.J.S. Sirinathsinghji in “NMDA antagonists as potential analgesic drugs,” D.J.S. Sirinathsinghji, R.G. Hill, Ed., Birkhauser Varlag, Boston, 2002, p.45. S. Boyce and N.M.J. Rupniak in “NMDA antagonists as potential analgesic drugs,” D.J.S. Sirinathsinghji, R.G. Hill, Ed., Birkhauser Varlag, Boston, 2002, p.147. C.N. Sang in “NMDA antagonists as potential analgesic drugs,” D.J.S. Sirinathsinghji, R.G. Hill, Ed., Birkhauser Verlag, Boston, 2002, p.165. H. Brauner-Osborne, J. Egebjerg, E.O. Nielsen, U. Madsen and P. Krogsgaard-Larsen, J. Med. Chem., a, 2609 (2000). D.J. Laurie and P.H. Seeburg, Eur. J. Pham-racol., a, 335 (1994). S.D. Donevan and R.T. McCabe, Mol. Pharmacol., s, 614 (2000). B. Wittekindt, S. Malany. R. Schemm, L. Otvos, M.L. Maccecchini, B. Laube and H. Bet& Neuropharmacology, 41,753 (2001). D. Donati and F. Micheli, Exp. Opin. Ther. Patents, 2.667 (2000). M. Honer, D. Benke, B. Laube, J. Kuhse, R. Heckendorn. H. Allgeier, C. Angst, H. Monyer, P.H. Seeburg, H. Betz and H. Mohler, J. Biol. Chem., 273, 11158 (1998). M. Quartaroli, N. Fasdelli, L. Bettelini. G. Maraia and M. Corsi, Eur. J. Pharmacol., 430, 219 (2001). M.S. Wallace, M.C. Rowbotham. N.P. Katz, R.H. Dworkin, R.M. Dotson, B.S. Galer, R.L. Rauck, MM. Backonja, S.N. Quessy and P.D. Meisner, Neurology, s, 1694 (2002).

Neuropathic

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Butera,

Brandt

9

Chap.

1

18. 19.

C.G. Parsons, W. Danysz and G. Quack, Neuropharmacology, 3,735 (1999). M.R. Walters, A.P.J. Bradford, J. Fischer and K.R. Lees, Br. J. Clin. Pharmacol., 53, 305 (2002). F. Menniti, B. Chenard, M. Collins, M. Ducat, I. Shalaby and F. White, Eur. J. Pharmacol.. 331.117 (1997). S. Boyce, A. Wyatt, J.K. Webb, R. O’Donnell, G. Mason, M. Rigby, D. Sirinathsinghji, R.G. Hill and N.M. Rupniak, Neuropharmacology, 38,611 (1999). R. Gill, A. Alanine, A. Bourson, B. Buttelmann, G. Fischer, M.P. Heitz, J.N.C. Kew, B. Levet-Trafit. H.P. Lorez, P. Malherbe, M.T. Miss, V. Mutel, E. Pinard, S. Roever, M. Schmitt, G. Trube, R. Wybrecht, R. Wyier and J.A. Kemp, J. Pharmacol. Exp. Ther., 302, 940 (2002). C.F. Claiborne, J.A. McCauley, B.E. Libby, N.R. Curtis, H.J. Diggle, J.J. Kulagowski, S.R. Michelson, K.D. Anderson, D.A. Claremon, R.M. Freidinger, R.A. Bednar, S.D. Mosser, S.L. Gaul, T.M. Connolly, C.L. Condra, B. Bednar, G.L. Stump, J.J. Lynch, A. Macaulay, K.A. Wafford, KS. Koblan and N.J. Liverton, Bioorg. Med. Chem. Lett., 13, 697 (2003). T.E. Salt, Drug Dev. Res., 54. 129 (2001). V. Mutel, Exp. Opin. Ther. Patents, 2, 1845 (2002). K. Walker, M. Bowes, M. Panesar, A. Davis, C. Gentry, A. Kesingland, F. Gasparini, W. Spooren. N. Stoehr. A. Pagano, P.J. Flor, I. Vranesic, K. Lingenhoehl, E.C. Johnson, M. Varney, L. Urban and R. Kuhn, Neuropharmacology, 40,l (2001). K. Fisher, M.E. Fundytus, C.M. Cahill and T.J. Coderre, Pain, 77,59 (1998). A. Dogrul, M.H. Ossipov, J. Lai, T.P. Malan and F. Porreca, Neurosci. Lett., 292, 115 (2000). J.H. Neale. T. Bzdega and B. Wroblewska, J. Neurochem., 75,443 (2000). S.R. Chen, K.M. Wozniak, B.S. Slusher and H.L. Pan, J. Pharmacol. Exp. Ther., 300, 662 (2002). W. Zhang, B. Slusher, Y. Murakawa, K.M. Wozniak, T. Tsukamoto, P.F. Jackson and A.A.F. Sima, J. Neurol. Sci., 194, 21 (2002). P.F. Jackson, K.M. Maclin, E. Wang, B.S. Slusher, R.S. Lapidus and P. Majer, WO Patent 0001668 (2000). T. Tsukamoto, P. Majer, D. Stoermer and B. Slusher, WO Patent 02057222 (2002). H. Vanegas and H. Schaible, Pain, 85, 9 (2000). J.D. England and H.J.I. Gould, Adv. Neurol., 88, 147 (2002). W.A. Catterall, Annu. Rev. Cell Dev. Biol., l6, 521 (2000). H. Saegusa, T. Kurihara, S. Zong, A. Kazuno. Y. Matsuda, T. Nonaka. W. Han, H. Toriyama and T. Tanabe, EMBO Journal, a,2349 (2001). S. Bowersox, N. Tich, M. Mayo and R. Luther, Drugs Future, 23,152 (1998). P. Favreau, N. Gilles. H. Lamthanh, R. Bournaud. T. Shimahara, F. Bouet. P. Laboute. Y. Letourneux, A. Menez, J. Molgo and F. Le Gall, Biochemistry, 40, 14567 (2001). M.T. Smith, P.J. Cabot, F.B. Ross, A.D. Robertson and R.J. Lewis, Pain, t& 119 (2002). Y. Song, S.S. Bowersox, D.T. Connor, D.J. Dooley, SM. Lotarski, T. Malone, G. Miljanich. E. Millerman, M.F. Rafferty, D. Rock, B.D. Roth, J. Schmidt, S. Stoehr, B.G. Szoke, C. Taylor, M. Vartanian and Y.X. Wang, J. Med. Chem., a,3474 (2000). T.P. Snutch, K.G. Sutton and G.W. Zamponi, Curr. Opin. Pharmacol., 1, 11 (2001) G. Wheeler, Curr. Opin. Invest. Drugs, 3,470 (2002). B.A. Lauria-Horner and R.B. Pohl, Exp. Opin. Invest. Drugs, l2, 663 (2003). H. Bolay and M.A. Moskowitz, Neurology, 2. S2 (2002). N.B. Finnerup. H. Gottrup and T.S. Jensen, Exp. Opin. Pharmacother., 3, 1411 (2002). J.C. Hunter in “Novel Aspects of Pain Management,” Sawynok, Cowan, Ed., Wiley-Liss, Inc., 1999, p.321. A.A. Elliott and J.R. Elliott, J. Physiol. (Lond). 463.39 (1993). J. Lai, M.S. Gold, C.S. Kim, D. Bian, M.H. Ossipov, J.C. Hunter and F. Porreca, Pain, 95, 143 (2002). S. Dib-Hajj, J.A. Black, T.R. Cummins and S.G. Waxman, Trends Neurosci., 2, 253 (2002). D.J. Trezise, V.H. John and X.M. Xie, Br. J. Pharmacol., 124,953 (1998). S.K. Choi, P.R. Fatheree, D.C. Green and D.E. Marquess, WO Patent 02057215A2 (2002). R.M. Eglen, J.C. Hunter and A. Dray, Trends Pharmacol. Sci., 3, 337 (1999). M.J. Coghlan, M. Gopalakrishnan and W.A. Carroll, Annu. Rep. Med. Chem., S. 11 (2001). C.C. Shieh, M. Coghlan, J.P. Sullivan and M. Gopalakrishnan, Pharmacol. Rev., 2. 557 (2000).

20. 21. 22.

23.

24. 25. 26.

27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55.

lo 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67.

68. 69. 70. 71. 72. 73. 74. 75. 76.

77. 78. 79. 80.

81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94.

Section

I-Central

Nervous

System

Diseases

Robertson,

Ed

C. Rundfeldt, R. Bartsch, A. Restock, C. Tober and R. Dost, U.S. Patent 6 117 900 (2000). Y.-J. WU, L.-Q. Sun, J. Chen, H. He, A. L’Heureux, P. Dextraze, G.G. Kinney, S.I. Dworetzky and P. Hewawasam, WO Patent 02096858Al (2002). A.D. Wickenden, G.C. Rigdon, G.A. Mcnaughton-Smith and M.F. Gross, WQ Patent 0110381-A2 (2001). A. Szallasi and P.M. Blumberg. Pharmacol. Rev., 51, 159 (1999). A. Szallasi. Drugs Aging, 18, 561 (2001). P.M. Zygmunt, I. Julius, I. Di Marzo and E.D. Hogestatt, Trends Pharmacol. Sci., 21, 43 (2000). E. Hogestatt and P. Zygmunt, U.S. Patent 0 019444Al (2002). M.H. Rashid, M. Inoue, S. Kondo, T. Kawashima, S. Bakoshi and H. Ueda, J. Pharmacol. Exp. Ther., 304,940 (2003). K.M. Walker, L. Urban, S.J. Medhurst, S. Patel, M. Panesar, A.J. Fox and P. McIntyre, J. Pharmacol. Exp. Ther., =,56 (2003). A.R. Santos and J.B. Calixto, Neurosci. Lett., =,73 (1997). M.N. Perkins and E.A. Campbell, Br. J. Pharmacol., 107,329 (1992). Y.G. Sue,T.U. Oh, H.D. Kim, J.W. Lee, H.G. Park, O.H. Park.Y.S. Lee.Y.H. Park, Y.H. Joo, J.K. Choi, K.M. Lim, S.Y. Kim, J.K. Kim, H.J. Koh, J.H. Moh, Y.S. Jeong, J.B. Yi and Y.I. Oh, WO Patent 0216318-Al (2002). A.J. Culshaw, P. Gull, A. Hallett, H.Y..Kim, M.P. Seiler, K. Zimmermann, Y. Liu and P. Mahavir, WO Patent 02076946A2 (2002). A. Hutchison, R.W. Desimone, K.J. Hodgetts, J.E. Krause and G.G. White, WO Patent 0208221 -A2 (2002). M. Thomoson and P.A. Wvman. WO Patent 02072536-Al (2002). K.A. Jacobson, M.F. Jarvis and’M. Williams, J. Med. Chem:, @,4057 (2002). M. Williams, E.A. Kowaluk and S.P. Arneric, J. Med. Chem., 2, 1481 (1999). G. Dell’Antonio, A. Quattrini, E. Dal Cin. A. Fulgenzi and M.E. Ferrero, Neurosci. Lett., 32J 87 (2002). P. Honore, J. Mikusa, B. Bianchi, H. McDonald, J. Cartmell, C. Faltynek and M.F. Jarvis, Pain, 96,99 (2002). B.A. Chizh and P. Illes, Pharmacol. Rev., 53,553 (2001). M.F. Jarvis, EC. Burgard, S. McGaraughty, P. Honore, K. Lynch, T.J. Brennan. A. Subieta, T. Van Biesen, J. Cartmell, B. Bianchi. W. Niforatos, K. Kage, H. Yu, J. Mikusa, CT. Wismer. C.Z. Zhu. K. Chu. C.H. Lee. A.O. Stewart, J. Polakowski. B.F. Cox. E. Kowaluk. M. ‘Williams, J. Sullivan and C. Faltynek. Proc. .Natl. Acad. Sci: U. S. A.,.99, 17179 (2002). M.D. Meyer, M.W. Decker, L.E. Rueter, D.J. Anderson, M.J. Dart, K.H. Kim, J.P. Sullivan and M. Williams, Eur. J. Pharmacol., 393. 171 (2000). R.L. Papke, J. Pharmacol. Exp. Ther., 301,765 (2002). M.I. Damaj, E.M. Meyer and B.R. Martin, Neuropharmacology, 39,2785 (2000). J.K. Myers, A.L. Bodnar, L.A. Cortes-Burgos, D.M. Dinh, V.E. Groppi, M. Hajos, N.R. Higdon, W.E. Hoffmann, R.S. Hurst, T.M. Wall, M.L. Wolfe and E. Wong, Abst. Pap. Am. Chem. Sot.. 225th ACS National Meeting I- MEDI-224 (2003). H.X. Liu, P. Brumovsky, R. Schmidt, W. Brown, K. Payza, L. Hodzic, C. Pou, C. Godbout and T. Hokefelt, Proc. Natl. Acad. Sci. U. S. A., 98.9960 (2001). T.A. Spalding, C. Trotter, N. Skjaerbaek. T.L. Messier, E.A. Currier, ES. Burstein, D.H. Li, U. Hacksell and M.R. Brann. Mol. Pharmacol., &l, 1297 (2002). T.A. Samad, A. Sapirstein and C.J. Woolf, Trends Mol. Med., 8, 390 (2002). E. Bastia, K. Varani, A. Monopoli and R. Bertorelli, Neurosci. Lett., 328,241 (2002). J.L. Croxford, CNS Drugs, u, 179 (2003). R. Przewlocki and B. Przewlocka, Eur. J. Pharmacol., =,79 (2001). A.P. Silva, C. Cavadas and E. Grouzmann, Clin. Chim. Acta, =,3 (2002). J.J. Idanpaan-Heikkila, G. Guilbaud and V. Kayser, J. Pharmacol. Exp. Ther., 282, 1366 (1997). C.M. Cahill and T.J. Coderre, Pain, 95, 277 (2002). D. Levy and D.W. Zochodne, Pain, as,265 (2000). K.J. Powell, W. Ma, M. Sutak, H. Doods, R. Quirion and K. Jhamandas, Br. J. Pharmacol., 131,875 (2000). T.J. Boucher and S.B. McMahon, Curr. Opin. Pharmacol., ?_, 66 (2001). T.L. Yaksh and P.R. Wilson, J. Pharmawl. Exp. Ther., 208,446 (1979). L. Bardin, J. Schmidt, A. Alloui and A. Eschalier, Eur. J. Pharmawl.. 409, 37 (2000).