ABSTRACT
We previously reported that a lipophilic N-(4'-hydroxy-3',5'-di-tert-butylbenzyl) derivative (1) of the voltage-gated sodium channel blocker mexiletine, was a more potent sodium channel blocker inâ vitro and inâ vivo. We demonstrate that replacing the chiral methylethylene linker between the amine and di-tert-butylphenol with an achiral 1,3-propylene linker (to give (2)) maintains potency inâ vitro. We synthesized 25 analogues bearing the 1,3-propylene linker and found that minor structural changes resulted in pronounced changes in state dependence of blocking human NaV 1.2 and 1.6 channels by high-throughput patch-clamp analysis. Compared to mexiletine, compounds 1 and 2 are highly selective NaV 1.2 inhibitors and >500 times less potent in inhibiting NaV 1.6 channels. On the other hand, a derivative (compound 4) bearing 2,6-dimethoxy groups in place of the 2,6-dimethyl groups found in mexiletine was found to be the most potent inhibitor, but is nonselective against both channels in the tonic, frequency-dependent and inactivated states. In a kindled mouse model of refractory epilepsy, compound 2 inhibited seizures induced by 6â Hz 44â mA electrical stimulation with an IC50 value of 49.9±1.6â mg kg-1 . As established sodium channel blockers do not suppress seizures in this mouse model, this indicates that 2 could be a promising candidate for treating pharmaco-resistant epilepsy.
Subject(s)
Benzylamines/chemical synthesis , Seizures/drug therapy , Voltage-Gated Sodium Channel Blockers/chemical synthesis , Voltage-Gated Sodium Channels/metabolism , Animals , Benzylamines/metabolism , Drug Stability , Electric Stimulation , Humans , Mexiletine/metabolism , Mice , Molecular Structure , Patch-Clamp Techniques/methods , Structure-Activity Relationship , Voltage-Gated Sodium Channel Blockers/metabolismABSTRACT
A new core-substituted naphthalene diimide (cNDI) compound that is sensitive to both H(+) and solvent polarity has been synthesised and characterised. Optical absorption and emission change upon protonation while emission quantum yield and decay kinetics of the unprotonated form vary significantly with solvent polarity due to delayed fluorescence.
ABSTRACT
Halide-templated tert-butylethynide Ag14 complexes undergo reversible exchange with copper(I) to afford a series of mixed Ag14-nCun (n = 1-6) species. Up to six silver atoms in the cluster can be replaced with copper(I) to give a core structure featuring a Ag8Cu6 rhombic dodecahedron. These clusters are useful models for investigating the chemical reactivity and photoluminescence of heterometallic d(10)-d(10) systems.
Subject(s)
Bromides/chemistry , Chlorides/chemistry , Copper/chemistry , Silver/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Crystallography, X-Ray , Ions/chemistry , Molecular ConformationABSTRACT
Solid-phase synthesis is greatly dependent on the solid support. Here, we report the use of a new hydrophilic grafted surface on SynPhase lanterns in solid-phase organic chemistry. A convenient and facile solid-phase synthesis of disubstituted 1,4-benzodiazepine-2-ones on polyamide SynPhase lanterns is described. The key step of the synthesis involved a reduction-cyclization of a nitroaryl methyl ester with a mixture of tin(II) chloride dihydrate and ammonium acetate in water and ethanol at elevated temperature to give the desired target compounds. A library of 21 disubstituted 1,4-benzodiazepine-2-ones was prepared.
