Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Nav1.8 have shown that this channel ...contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC₅₀ = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Nav1.8 (IC₅₀ = 8 nM) and was >100-fold selective vs. human Nav1.2, Nav1.3, Nav1.5, and Nav1.7 (IC₅₀ values >=1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED₅₀ = 47 mg/kg, i.p.), sciatic nerve injury (ED₅₀ = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED₅₀ almost equal to 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED₅₀ = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Nav1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
Long-lived individuals and their offspring have healthier metabolic characteristics than expected, such as more favorable levels of fasting glucose, insulin, and lipids than controls without ...longevity. Dysregulation in metabolic pathways has also shown to predict accelerated aging. Using information from the Long Life Family Study (LLFS), a multi-center study of two-generation families selected for exceptional longevity, we developed an indicator of healthy metabolism to determine whether metabolic health was more prevalent in a subset of LLFS families and whether it was heritable and associated with other metrics of healthy aging.
A Latent Profile Analysis was applied to age- and gender-adjusted z-scores of fasting levels of glucose, insulin, triglycerides, and high-density lipoprotein cholesterol, body mass index, waist circumference, interleukin-6, and C-reactive protein. Families were defined as meeting the healthy metabolic phenotype if ≥2 and ≥50% of their offspring were classified into a latent subgroup with a profile of healthier metabolic markers than expected given age and gender relative to all LLFS offspring.
The log odds of being classified into the latent subgroup with a healthy profile of metabolic markers was heritable (h2 = 0.40, p < 0.001). Among 388 families, 39 (10%) met the healthy metabolic phenotype. Participants from these families had somewhat better cognition than those from remaining families. Proband-generation participants from families who met the healthy metabolic phenotype also had better pulmonary functioning and physical performance.
The better cognition, pulmonary function, and physical performance among probands from families with the healthy metabolic phenotype may indicate that this subset of LLFS families have a more extreme longevity phenotype than other LLFS families since cognitive, physical, and pulmonary function are top mortality predictors for older adults. Future work is needed to determine if rare or protective alleles confer a healthy metabolic phenotype in this subset of LLFS families with exceptional metabolism.
•A healthy metabolic phenotype was heritable (h2 = 0.40, p < 0.001).•10% of families had ≥2 and ≥50% of offspring classified as metabolically healthy.•Probands from families with healthy metabolism had better physical performance.
A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the ...anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Nav1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the ...anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the ...pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
.
The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the ...tetrodotoxin-resistant sodium channel Na
v1.8 (PN3) as well as the Na
v1.2 and Na
v1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na
v
1.8 have shown that this ...channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC
50
= 140 nM) and the generation of spontaneous and electrically evoked action potentials
in vitro
in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na
v
1.8 (IC
50
= 8 nM) and was >100-fold selective vs. human Na
v
1.2, Na
v
1.3, Na
v
1.5, and Na
v
1.7 (IC
50
values ≥1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED
50
= 47 mg/kg, i.p.), sciatic nerve injury (ED
50
= 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED
50
≈ 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED
50
= 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na
v
1.8 sodium channels
in vivo
produces significant antinociception in animal models of neuropathic and inflammatory pain.
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against${\rm Na}_{{\rm v}}1.8$have shown ...that this channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC₅₀ = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human${\rm Na}_{{\rm v}}1.8$(IC₅₀ = 8 nM) and was > 100-fold selective vs. human${\rm Na}_{{\rm v}}1.2$,${\rm Na}_{{\rm v}}1.3$,${\rm Na}_{{\rm v}}1.5$, and${\rm Na}_{{\rm v}}1.7$(IC₅₀ values ≥1 μM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED₅₀ = 47 mg/kg, i.p.), sciatic nerve injury (ED₅₀ = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED₅₀ ≈ 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED₅₀ = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of${\rm Na}_{{\rm v}}1.8$sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
Activation of tetrodotoxin-resistant sodium channels contributes to action potential electrogenesis in neurons. Antisense oligonucleotide studies directed against Na sub(v)1.8 have shown that this ...channel contributes to experimental inflammatory and neuropathic pain. We report here the discovery of A-803467, a sodium channel blocker that potently blocks tetrodotoxin-resistant currents (IC sub(50) = 140 nM) and the generation of spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. In recombinant cell lines, A-803467 potently blocked human Na sub(v)1.8 (IC sub(50) = 8 nM) and was >100-fold selective vs. human Na sub(v)1.2, Na sub(v)1.3, Na sub(v)1.5, and Na sub(v)1.7 (IC sub(50) values greater than or equal to 1 mu M). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED sub(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED sub(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED sub(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED sub(50) = 41 mg/kg, i.p.). A-803467 was inactive against formalin-induced nociception and acute thermal and postoperative pain. These data demonstrate that acute and selective pharmacological blockade of Na sub(v)1.8 sodium channels in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.
Committee Reports 1929-30 Babcock, Julia G.; Baker, Mary E.; Marron, Joseph F. ...
Bulletin of the American Library Association,
05/1930, Letnik:
24, Številka:
5
Journal Article
PDF
