Molecular Insights into the Local Anesthetic Receptor within Voltage-Gated Sodium Channels Using Hydroxylated Analogs of Mexiletine

We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, directly blocked voltage-gated sodium channels, whereas salbutamol and nadolol did not (Desaphy et al., 2003), suggesting the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. To verify such an hypothesis, we synthesized five new mexiletine analogs by adding one or two hydroxyl groups to the aryloxy moiety of the sodium channel blocker and tested these compounds on hNav1.4 channels expressed in HEK293 cells. Concentration–response relationships were constructed using 25-ms-long depolarizing pulses at −30 mV applied from an holding potential of −120 mV at 0.1 Hz (tonic block) and 10 Hz (use-dependent block) stimulation frequencies. The half-maximum inhibitory concentrations (IC50) were linearly correlated to drug lipophilicity: the less lipophilic the drug, minor was the block. The same compounds were also tested on F1586C and Y1593C hNav1.4 channel mutants, to gain further information on the molecular interactions of mexiletine with its receptor within the sodium channel pore. In particular, replacement of Phe1586 and Tyr1593 by non-aromatic cysteine residues may help in the understanding of the role of π–π or π–cation interactions in mexiletine binding. Alteration of tonic block suggests that the aryloxy moiety of mexiletine may interact either directly or indirectly with Phe1586 in the closed sodium channel to produce low-affinity binding block, and that this interaction depends on the electrostatic potential of the drug aromatic tail. Alteration of use-dependent block suggests that addition of hydroxyl groups to the aryloxy moiety may modify high-affinity binding of the drug amine terminal to Phe1586 through cooperativity between the two pharmacophores, this effect being mainly related to drug lipophilicity. Mutation of Tyr1593 further impaired such cooperativity. In conclusion, these results confirm our former hypothesis by showing that the presence of hydroxyl groups to the aryloxy moiety of mexiletine greatly reduced sodium channel block, and provide molecular insights into the intimate interaction of local anesthetics with their receptor

Nuovi rinvenimenti di ceramica euboica a Naxos di Sicilia

I materiali di seguito analizzati sono un semplice e ancor più breve addendum alla ricca ed articolata rassegna di ceramica tardo-geometrica dagli scavi di Naxos, che nel 1976 Paola Pelagatti presentava in questa stessa sede. La quantità, la qualità e la varietà dei ritrovamenti rivelavano la colonia come il sito della Sicilia maggiormente interessato da ceramica euboica e di tipo euboico. Qui viene preso in considerazione un ristretto nucleo di frammenti. Si tratta principalmente di vasi ape..

Resti di capanne della tarda età del Ferro a Naxos di Sicilia

Forthcoming

Recording and Reconstructing the Sacred Landscapes of Sicilian Naxos

In recent years, an on-going project investigating the urban landscape of Naxos has surveyed and produced several new digital reconstructions of the settlement's simple non-peripteral temples, most with highly decorative roofs. Three Archaic sacred buildings of Sicilian Naxos are used to demonstrate different approaches to recording the remains and reconstructing their architectural features. This work reflects changes in digital strategies over the past ten years. Tempietto H is a small shrine located outside the city's boundaries and the site is currently inaccessible, so its reconstruction is based on excavation documentation and roof terracottas. The visible half of Tempietto C was documented using three-dimensional line-drawing with total stations and photogrammetry; the back-filled south-western part was surveyed with ground penetrating radar. Temple B is the largest sacred structure in Naxos. A geophysical survey gives new data on the eastern extent of the sanctuary. The area has been recorded with handheld and aerial photography to create a three-dimensional model of the sanctuary. A new orthogonal grid of the city was established circa 470 BCE and a rectangular base was placed in the south-east corner of every crossroad. These bases were the starting point for the plan, and their interpretation as altars converts the entire urban plan into a sacred landscape.Peer reviewe

Recording and Reconstructing the Sacred Landscapes of Sicilian Naxos

In recent years, an on-going project investigating the urban landscape of Naxos has surveyed and produced several new digital reconstructions of the settlement’s simple non-peripteral temples, most with highly decorative roofs. Three Archaic sacred buildings of Sicilian Naxos are used to demonstrate different approaches to recording the remains and reconstructing their architectural features. This work reflects changes in digital strategies over the past ten years. Tempietto H is a small shrine located outside the city’s boundaries and the site is currently inaccessible, so its reconstruction is based on excavation documentation and roof terracottas. The visible half of Tempietto C was documented using three-dimensional line-drawing with total stations and photogrammetry; the back-filled south-western part was surveyed with ground penetrating radar. Temple B is the largest sacred structure in Naxos. A geophysical survey gives new data on the eastern extent of the sanctuary. The area has been recorded with handheld and aerial photography to create a three-dimensional model of the sanctuary. A new orthogonal grid of the city was established circa 470 BCE and a rectangular base was placed in the south-east corner of every crossroad. These bases were the starting point for the plan, and their interpretation as altars converts the entire urban plan into a sacred landscape

L'editoria napoletana e le trasformazioni del secolo XIX. Esperienze a confronto: Migliaccio, Raimondi, De Simone

De Simone, Raimondi, Migliaccio, tre stampatori che riuscirono a sopravvivere alle profondi mutamenti e alle innumerevoli fratture tra ottocento e novecento. Si analizzano le dinamiche, spesso differenti, che permisero loro di sopravvivere ai mutamenti del temp