Park, Ki Duk Yang, Xiao-Fang Lee, Hyosung Dustrude, Erik T. Wang, Yuying Khanna, Rajesh Kohn, Harold 2024-01-20T13:01:21Z 2024-01-20T13:01:21Z 2021-08-31 2013-03 1948-7193 https://pubs.kist.re.kr/handle/201004/128339 Lacosarnide ((R)-1) is a recently marketed, first-in-class, antiepileptic drug. Patch-clamp electrophysiology studies are consistent with the notion that (R)-1 modulates voltage-gated Na+ channel function by increasing and stabilizing the slow inactivation state without affecting fast inactivation. The molecular pathway(s) that regulate slow inactivation are poorly understood. Affinity baits are chemical reactive units, which when appended to a ligand (drug) can lead to irreversible, covalent modification of the receptor thus permitting drug binding site identification including, possibly, the site of ligand function. We describe, herein, the synthesis of four (R)-1 affinity baits, (R)-N-(4 ''-isothiocyanatobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-8), (S)-N-(4 ''-isothiocyanatobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((S)-8), (R)-N-(3 -isothiocyanatobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-9), and (R)-N-(3 ''-acrylamidobiphenyl-4'-yl)methyl 2-acetamido-3-methoxypropionamide ((R)-10). The affinity bait compounds were designed to interact with the receptor(s) responsible for (R)-1-mediated slow inactivation. We show that (R)-8 and (R)-9 are potent inhibitors of Na+ channel function and function by a pathway similar to that observed for (R)-1. We further demonstrate that (R)-8 function is stereospecific. The calculated IC50 values determined for Na+ channel slow inactivation for (R)-1, (R)-8, and (R)-9 were 85.1, 0.1, and 0.2 mu M, respectively. Incubating (R)-9 with the neuronal-like CAD cells led to appreciable levels of Na+ channel slow inactivation after cellular wash, and the level of slow inactivation only modestly decreased with further incubation and washing. Collectively, these findings have identified a promising structural template to investigate the voltage-gated Na+ channel slow inactivation process. English AMER CHEMICAL SOC RECEPTOR MEDIATED PHENOMENA SLOW INACTIVATION ANTICONVULSANT ACTIVITIES IRREVERSIBLE LIGANDS DELTA-OPIATE MU-OPIATE PROBES IDENTIFICATION INHIBITORS BINDING Discovery of Lacosamide Affinity Bait Agents That Exhibit Potent Voltage-Gated Sodium Channel Blocking Properties Article 10.1021/cn300188h 1 ACS CHEMICAL NEUROSCIENCE, v.4, no.3, pp.463 - 474 ACS CHEMICAL NEUROSCIENCE 4 3 463 474 scie scopus 000316594100012 2-s2.0-84875527344 Biochemistry & Molecular Biology Chemistry, Medicinal Neurosciences Biochemistry & Molecular Biology Pharmacology & Pharmacy Neurosciences & Neurology Article RECEPTOR MEDIATED PHENOMENA SLOW INACTIVATION ANTICONVULSANT ACTIVITIES IRREVERSIBLE LIGANDS DELTA-OPIATE MU-OPIATE PROBES IDENTIFICATION INHIBITORS BINDING Anti-epileptic lacosamide affinity bait agent irreversible modification voltage-gated sodium channel slow inactivation