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-Tvpe 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 (T-type) (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 Cav2.2 gene in mice decreased the magnitude of inflammatory and neuropathic pain behaviors (37). Ziconotide (SNX-111), an amino acid co-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 (ED50 = 0.11 nmol) after i.t. administration in the rat hind paw model (40). Although its efficacy was comparable to SNX-111, AM336 did not exhibit a biphasic dose-response curve like SNX-111; most likely due to its enhanced selectivity for the N-type VGCC.
Two recently reported non-peptidic N-type VGCC blockers (10 and 11) possessed antinociceptive effects in pain models. Compound 10 had anti-writhing effects with an EDso = 6 mg/kg (i.t.) in rats. Compound 11 (IC50 = 1.5 nM in IMR32 assay) was efficacious in the anti-writhing (ED50 = 4.5 mg/kg, ¡.v.), SNL (ED50 = 23 ng, i.t.), and formalin (ED50 = 16 mg/kg, i.v.) pain models (41). However, both compounds also posses modest Na* channel blocking properties (42). Gabapentin (12) represents another class of VGCC modulators, although the mechanism of action is not fully understood. It appears to bind to a2/8 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 a2/8-selective binder, has shown efficacy for various conditions associated with pain, seizures, and anxiety (44).
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 subtype-selective VGSC blockers. Multiple VGSC subtypes are expressed in DRG neurons including rapidly inactivating, TTX-sensitive (TTX-S), and slowly inactivating, TTX-resistant (TTX-R; Nav1.8 and Nav1.9) channels (47). Expression of TTX-R channels is restricted predominately to sensory neurons (48). Antisense oligodeoxynucleotide knockdown of the expression of Nav1.8 reversed SNL-induced allodynia and hyperalgesia (49). Nav1 -9 has recently been implicated in hyperexcitability after nerve injury (50). Although highly selective TTX-R compounds have not been reported, BW 4030W92 (13) shows slight selectivity for this subtype of NaCh (51). Several recent patent applications have disclosed VGSC blockers that were active in neuropathic pain models (52). 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 and subsequent decrease in neuronal excitability. The role for K* channel 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 KCNQ2/KCNQ3 heteromultimeric channel is expressed predominately in neurons, whereas KCNQ3/KNCQ4/KNCQ5 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 mg/kg of 14 was comparable to the effect caused by 60 mg/kg of oral gabapentin (56). Compounds 15-18 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).
Compounds in a series of pyridyi-benzamides (19) disclosed as selective KCNQ2/KCNQ3 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 mg/kg, although specific data for compounds were not revealed (58).
Vanilloid Receptor Modulators - The vanilloid receptor (VR1) is a member of the transient receptor potential (TRP) family of non-selective cation channels. Capsaicin (20), a natural product derived from hot peppers, acts as an agonist at vanilloid receptors (TRPVR1) located on primary afferent nociceptors (59). In addition to being sensitive to 20, TRPVR1 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 (21J has agonist effects at TRPVR1 receptors (61). Numerous related fatty-acid analogs of 2^ which also have modulatory effects on TRPVR1 have recently been described (62). Resiniferatoxin (22) represents yet another, structurally distinct TRPVR1 agonist, which has been studied clinically (59).
The physiology and pharmacology of TRPVRs suggest that both agonists and antagonists might be useful for treating painful conditions. Peripheral TRPVR1 s are expressed primarily on unmyelinated C-fibers; however, reported increased expression of TRPVR1 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 TRPVR1 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 23 in rat neuropathic pain models suggested limited activity, more recent studies in guinea pig neuropathic pain models indicate greater activity of 23 (64,66). Numerous series of very closely related urea derivatives have recently been reported as TRPVR1 antagonists possessing activity in rodent pain models. Compounds 24 and 25 represent examples in a series of thioureas that reportedly decreased writhing by greater than 90% at i.p. doses between 3 and 10 mg/kg in the mouse writhing test (67). The pyrido-pyrimidinone compound 26 (IC50 = 65 nM) dose-dependently reduced mechanical hyperalgesia after p.o. doses between 0.3 and 30 mg/kg (68). Finally, a series of 2-pyridinyl-piperazine derived ureas and ethylene-diamine-derived ureas, illustrated by structures 27 and 28, respectively, were claimed as potent TRPVR1 antagonists (69,70).
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