Chimeric Agents Derived from the Functionalized Amino Acid, Lacosamide, and the α-Aminoamide, Safinamide: Evaluation of Their Inhibitory Actions on Voltage-Gated Sodium Channels, and Antiseizure and Antinociception Activities and Comparison with Lacosamide and Safinamide

Abstract

The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7–(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7–(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7–(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats.

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

“…We have reported on a novel series of chimeric compounds, ( R )- A , 8–10 derived from the merger of key structural units (Fig. 1B, C) present in the functionalized amino acid (FAA), lacosamide 11 (( R )- N -benzyl 2- N -acetamido-3-methoxypropionamide, ( R )- 1 ) and the α-aminoamide (AAA), safinamide 12,13 (( S )-2-(4′-((3″-fluoro)benzyloxy)benzyl)aminopropionamide, ( S )- 2 ).…”

“…We demonstrated that select ( R )- A compounds displayed potent anticonvulsant activities in the maximal electroshock 18 (MES) and the 6-Hz psychomotor 19 seizure assays in rodents. 8–10 The anticonvulsant activities of ( R )- A have been attributed, in part, to their actions on voltage-gated sodium channel (VGSC) properties. 9,10,20 Chimeric compounds ( R )- A potently transitioned VGSCs to the slow-inactivated state and in some cases, affected fast inactivation processes and inhibited Na + currents in a frequency (use)-dependent fashion.…”

“…8–10 The anticonvulsant activities of ( R )- A have been attributed, in part, to their actions on voltage-gated sodium channel (VGSC) properties. 9,10,20 Chimeric compounds ( R )- A potently transitioned VGSCs to the slow-inactivated state and in some cases, affected fast inactivation processes and inhibited Na + currents in a frequency (use)-dependent fashion. The experimental findings for slow inactivation by ( R )- A were also consistent with a mechanism in which the chimeric compounds block fast-inactivated channels with very slow kinetics.…”

“…8 Thus, we further investigated the activities of ( R )- A compounds wherein the linker (L) was either a single bond 9 or an oxymethylene (OCH 2 ) 10 group and found that the X-substituent in the terminal aromatic ring influenced the cellular and whole animal pharmacological activities. Here, we explore the ( R )- A series that contain an oxy (O)-linker to give ( R )- D .…”

“…Electrophysiology studies showed that ( R )- D displayed sodium channel properties consistent with other members of this general class of compounds. 9,10,20 …”