RESUMO
In many cases, the hybridization of two or more excitation modes in solids has led to new and useful dispersion relations of waves. Well-studied examples are phonon polaritons, plasmon polaritons, particle-plasmon polaritons, cavity polaritons, and magnetic resonances at optical frequencies. In all of these cases, the lowest propagating mode couples to a finite-frequency localized resonance. Herein, the unusual metamaterial phonon dispersion relations arising from the hybridization of an ordinary acoustical phonon mode with a back-folded soft or easy phonon mode of a monomode elastic metamaterial are discussed. Conceptually, the single easy mode can have strictly zero wave velocity. In reality, its wave velocity is very much smaller than that of all other modes. Considering polymeric three-dimensional printed elastic monomode metamaterials at ultrasound frequencies, it is shown theoretically and experimentally that the resulting pronounced avoided crossing, with a frequency splitting comparable to the mid-frequency, leads to backward-wave behavior for the lowest band over a broad frequency range, conceptually at zero loss.
RESUMO
Aryl sulfonamido tetralins based on lead compound 2a were synthesized and evaluated for Kv1.5 inhibitory activity. Several compounds having IC(50) values less then 0.1 microM were identified. Kv1.5 inhibitors have the potential to be atrium-selective agents for the treatment of atrial fibrillation.
Assuntos
Antiarrítmicos/síntese química , Canal de Potássio Kv1.5/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/síntese química , Sulfonamidas/síntese química , Tetra-Hidronaftalenos/síntese química , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Humanos , Canal de Potássio Kv1.5/metabolismo , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologiaRESUMO
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.
Assuntos
Amidas/síntese química , Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Furanos/síntese química , Bloqueadores dos Canais de Sódio/síntese química , Canais de Sódio/fisiologia , Amidas/química , Amidas/farmacologia , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , Furanos/química , Furanos/farmacocinética , Furanos/farmacologia , Gânglios Espinais/citologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.8 , Proteínas do Tecido Nervoso/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Dor/tratamento farmacológico , Dor/etiologia , Técnicas de Patch-Clamp , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-AtividadeRESUMO
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(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 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.
Assuntos
Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Furanos/química , Furanos/farmacologia , Neuralgia/tratamento farmacológico , Piperazinas/química , Piperazinas/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Analgésicos não Narcóticos/síntese química , Animais , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Furanos/síntese química , Humanos , Masculino , Camundongos , Piperazinas/síntese química , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/síntese química , Relação Estrutura-AtividadeRESUMO
Root-knot nematodes are a major group of plant-parasitic nematodes, but their sister group within the Tylenchida remains to be identified. To find the sister group and for any investigation of the evolutionary biology of the genus Meloidogyne, it would be useful to identify the most basal species within Meloidogyninae. Meloidogyne spartinae, a root-knot nematode parasitic on cordgrass (Spartina spp.), constitutes a potentially interesting early diverging (or at least highly divergent) root-knot nematode because it was originally described in a different genus, Hypsoperine (and later Spartonema), due to its unique anatomy and biology (although it was later put in synonymy by some, but not all, taxonomists). We have sequenced the whole 18S rDNA of this species and compared it to other sequences of this region that are available in GenBank for numerous Meloidogyne species. Phylogenetic analysis unambiguously locates the branch corresponding to M. spartinae as a lately diverging species, more closely related to M. maritima, M. duytsi or the M. ardenensis-hapla group. Thus, the distinction of a separate genus (Hypsoperine or Spartonema) for this species is not justified.
RESUMO
A collection of aryl sulfonamido indanes based on the lead compound 1 was synthesized and evaluated for Kv1.5 inhibitory activity. Kv1.5 inhibitors have the potential to be atrium-selective agents for treatment of atrial fibrillation. (1R,2R)-1 has an IC(50) of 0.033microM against Kv1.5 and is selective against other cardiac ion channels, including hERG.