Chimeric derivatives of functionalized amino acids and α-aminoamides: Compounds with anticonvulsant activity in seizure models and inhibitory actions on central, peripheral, and cardiac isoforms of voltage-gated sodium channels

Abstract

Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4′-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4′-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI = TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNav1.1, rNav1.3, hNav1.5, or hNav1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.

Synthesis and anticonvulsant activity of phenoxyacetyl derivatives of amines, including aminoalkanols and amino acids

“…In order to obtain compounds 8-11 and 17, the ester groups of compounds IIa-IId were hydrolysed with 10% NaHCO 3 (8 and 9) at room temperature (6-8 h) or were subjected to aminolysis with use of NH 3(aq conc) (10,17) or methylamine (11) with the addition of methanol. The precipitated final products were recrystallized from a hexane-toluene (1 : 1) mixture.…”

(−)-Hardwickiic Acid and Hautriwaic Acid Induce Antinociception via Blockade of Tetrodotoxin-Sensitive Voltage-Dependent Sodium Channels

“…To test whether the extracts (−)-HDA and HTA had effects on different sodium channels subtypes, we examined the effects of these compounds at a 20 μM concentration on peak current, steady-state activation, and fast inactivation in human embryonic kidney 293 (HEK293) cells that stably expressed cardiac (hNav1.5) and central nervous system (hNav1.1, rNav1.3) channels using voltage protocols previously reported . We observed that (−)-HDA had inhibitory effects on all NaV1.x currents tested; representative currents are shown in Figure A, E, and I (Figure B, C, NaV1.1:0.1% DMSO: −57.2 ± 9.2 mV versus (−)-HDA: −30.1 ± 5.1 mV; Figure F, G, NaV1.3:0.1% DMSO: −99.8 ± 14.6 mV versus (−)-HDA: −45.4 ± 6.3 mV; Figure J, K, NaV1.5:0.1% DMSO: −571.1 ± 86.6 mV versus (−)-HDA: −330.8 ± 60.9 mV).…”

A convenient synthesis of novel amino acid derivatives with potential antibacterial activity using sustainable materials

“…Amino acid derivatives have been reported to be biologically active as antibacterials, [14][15][16] antifungals 17,18 and antioxidants, 19 pseudo-analogues of the naturally occurring antibiotic sparsomyci, 20 anti-inflammatory 21 and anti-convulsant 22 agents. They are used also as reactive substrates in the design of bioactive molecules for cancer treatment.…”