Section I Central Nervous System Diseases

The Peripheral Neuropathy Solution

Dr. Labrum Peripheral Neuropathy Program

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

Chapter 1. Current and Emerging Opportunities for the Treatment of Neuropathic Pain

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 NR1 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 NR1 and NR2 subunits (5). Recently NR3A and NR3B subunits have been identified, which confer distinct channel activity when combined with NR1 (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 Antagonists - Preclinical and clinical studies demonstrate that competitive glutamate antagonists reverse hypersensitivity associated with neuropathic pain states (8,9). In general, most competitive glutamate site 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 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-(-)-(£)-4-(3-phosphonoprop-2-enyl) piperazine-2-carboxylic acid (CPPene) and selfotel exhibit 20 to 40-fold subunit selectivity for NR1/NR2A or NR2B over NR1/NR2C or NR2D (11). However, little separation is typically observed between NR1/NR2A over NR1/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 NR1/NR2B 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 Glycine Site Antagonists - NMDARs require glutamate, as well as the co-agonist 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 NR1 subunit, the azido- Ph probe i (CGP-51594) has been described as a glycine antagonist having 10-fold higher selectivity for NR1/NR2B subunits than for NR1/NR2A subunits (15).

Activity of 1 for blocking pain has not been published, however GV-196771A (2) reversed chronic constriction injury (CCI) of the sciatic nerve-induced thermal and tactile hypersensitivity after p.o. doses of 1-10 mg/kg (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 displaces [3H]-MK-801 binding from rat membranes with a Ki of approximately 1 nM (18). Memantine was effective in reversing CCI-induced thermal and SNL-induced 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

(18). CNS 5161 (31 is another channel blocker that 2

has a Ki of 1.8 nM in its ability to displace [3H]-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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