Figure 9 Antagonists for excitatory amino acid (glutamate) receptors.
tolerance related to prolonged opioid use. As noted above, late stage clinical trials of a dextromethorphan/morphine combination (MorphiDex) are ongoing. Antagonists of the kainic acid subtype of the glutamate receptor include LY 293558 (Figure 9) which was active in acute migraine.77
Modulation of N-type (Cav2.2) calcium channels has been shown to provide an avenue for development of novel analgesics, as exemplified by ziconotide, a 25 amino acid polycationic peptide originally isolated from the venom of a cone snail. Its delivery is limited to the epidural and intrathecal routes, as systemic administration has led to a risk for orthostatic hypotension.78 Ziconotide is approved for treating intractable cancer pain and chronic neuropathic pain. The clinical efficacy of ziconotide provides important validation of this novel analgesic mechanism. In addition to N-type calcium channels, T-type channels (Cav3.1 and Cav3.2) have also been implicated in nociceptive processing. T-type calcium channels are expressed on dorsal root ganglion neurons and intrathecal antisense treatment targeting the Cav3.2 subtype of T-type calcium channels effectively blocked all low-voltage calcium currents in dorsal root ganglion neurons and significantly attenuated both acute and inflammatory pain.79
Marijuana (cannabis) has been used to relieve pain for centuries.80 However, clinical evaluation of the major active cannabinoid, D9-tetrahydrocannabinol (D9-THC), has produced equivocal results in chronic cancer pain patients. Furthermore, the analgesic actions of D9-THC could not be clearly separated from the other well-described psychotropic actions of D9-THC. Investigation of the pharmacological actions of the cannabinoids has been greatly aided by the recent discovery of specific cannabinoid receptor subtypes (CB1 and CB2), elucidation of their signal transduction pathways, and the identification of putative endogenous ligands (e.g., anandamide).80 High densities of CB1 receptors are found in the CNS, while CB2 receptors are localized primarily to immune cells and peripheral nerve terminals. These advances in cannabinoid pharmacology suggest the possibility of identifying receptor subtype selective ligands.
Cannabimimetics have been shown to produce antinociception in animal pain models via spinal and supraspinal actions on CB1 receptors, and by peripheral actions at CB2 receptors on sensory afferents and, indirectly, on immune cells. Recent compounds in preclinical development include agonists with improved oral bioavailability and/or enhanced receptor subtypes selectivity. CT-3 (Figure 10) is an orally active and nonselective analog of THC that dose-dependently reduces acute nociception in the rat. Recently, CT-3 has been tested in the clinic in a phase II trial in chronic neuropathic pain patients and the results suggested that CT-3 could be useful in treating this condition.80 0-1057 (Figure 10) is a potent and moderately CB1 receptor selective analog of CT-3 that has improved water solubility and acute antinociceptive actions.67 HU-308 (Figure 10) is a novel, highly CB2 receptor selective agonist
(Ki CB1 > 10 mM, CB2 = 23 nM) that has antinociceptive effects in the persistent phase of the mouse formalin test, but was inactive in the acute phase of the formalin test.81 While no effects of HU-308 were observed on motor function, antinociceptive doses of the compound also reduced GI motility and blood pressure.82
More recently, the potential analgesic profile of CB2 agonists has been extensively characterized in in vivo pain models in rodents. PRS-211375 (Figure 10) has been shown to be CB2 selective (CB2 Ki = 9 nM; CB1 Ki = 300 nM) and a full agonist in adenylyl cyclase and GTPgS binding assays with similar potencies as observed in binding assays. PRS-211375 has good CNS penetration and has shown efficacy in various animal models including formalin, neuropathic pain models, acute thermal pain, visceral pain, and CFA-induced arthritis. PRS-211375 recently completed phase I clinical trial. AM-1241 (Figure 10) is another selective CB2 agonist used in preclinical models to identify the potential analgesic profile of CB2 agonists. This compound has been shown to decrease acute, inflammatory, and neuropathic pain, its effects mediated through the release of b-endorphin and effects on opioid receptors.84 GW405833 (Figure 10), another CB2 agonist, has also been shown to produce analgesia in animal models of chronic pain including postoperative pain. However, contrary to the results obtained with AM-1241, the analgesic effects of GW405833 are not mediated through activity at opioid receptors.85
The activation of voltage-gated sodium channels is necessary for the generation of neuronal action potentials. A feature common to the local anesthetics and most analgesic adjuvants (e.g., carbamazepine, lamotrigine, and amitriptyline) is their ability to block sodium channels and this property may underlie the clinical utility of these agents in reducing pain. However, all of these agents possess other pharmacologically relevant activities that results in limits their analgesic effectiveness in the clinic. Notably, these include CNS sedation and/or untoward cardiovascular effects.
The cloning and characterization of several sensory nerve-specific sodium channel subtypes has raised interest in the possibility of developing subtype-specific inhibitors which might overcome the cardiovascular and proconvulsant liabilities of nonselective agents. The voltage-gated sodium channel gene family consists of multiple members, termed Nav1.1 through Nav1.9.86 At least six of these channels are found in the peripheral nervous system.87 Structurally, the family has a high overall degree of similarity (around 50% identity), with subfamilies being very closely related (up to 90% identity). Susceptibility to blockade by natural toxins, particularly tetrodotoxin (TTX), has been typically used to classify sodium channel currents. Two TTX-resistant channels are present in the periphery: Nav1.8 (also called PN3 or SNS) and Nav1.9 (also called NaN). Nav1.8 is likely to be the more important sodium channel in regulating nociceptive signaling since in vivo antisense experiments targeting Nav1.9 did not reduce chronic neuropathic pain.88 Nav1.8 immunoreactivity is increased in the carrageenan inflammatory pain model, and increased proximal to the site of nerve injury in rats and humans. Antisense oligonucleotides against Nav1.8 prevented thermal hyperalgesia or mechanical allodynia from developing in animal models of neuropathic pain, and were also effective at reducing prostaglandin-induced hyperalgesia. Nav1.8 knockout mice demonstrated a diminished response to noxious mechanical stimuli and delayed inflammatory hyperalgesia. While the PN3/SNS subtype has been a major focus of research, other sodium channels may also be appealing targets for pharmaceutical intervention of pain.89,90 These data indicate that the development of antagonist that are selective for specific sodium channel subunits, like Nav1.8 may provide novel analgesic agents. The feasibility of this approach is likely to be difficult based on the poor selectivity of currently available sodium channel blockers, however, two NCEs have been recently described that show increased potency for tetrodotoxin-resistant sodium channels as compared to the typical analgesic adjuvants. Ralfinamide (NW-1029) (Figure 11) inhibits TTX-resistant currents in rat dorsal root ganglion neurons with an IC50 value of 10 mM and dose-dependently reduced allodynia in neuropathic pain models. CDA-54 ( ) is a potent (IC50 ~200nM)
nonselective sodium channel blocker that reduces pain in inflammation pain models.92
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