Lacosamide Isothiocyanate-Based Agents: Novel Agents To Target and Identify Lacosamide Receptors

Park, Ki Duk, Morieux, Pierre, Salome, Christophe, Cotten, Steven W, Reamtong, Onrapak, Eyers, Claire ORCID: 0000-0002-3223-5926, Gaskell, Simon J, Stables, James P, Liu, Rihe and Kohn, Harold (2009) Lacosamide Isothiocyanate-Based Agents: Novel Agents To Target and Identify Lacosamide Receptors. JOURNAL OF MEDICINAL CHEMISTRY, 52 (21). pp. 6897-6911.

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Abstract

(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults. Whole animal pharmacological studies have documented that (R)-2 function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogues, 3, which contain "affinity bait (AB)" and "chemical reporter (CR)" functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide ((R)-9), exhibited excellent seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2.

Item Type:	Article
Uncontrolled Keywords:	Brain, Animals, Mice, Inbred ICR, Mice, Seizures, Acetamides, Isothiocyanates, Intercellular Signaling Peptides and Proteins, Serine, Nerve Tissue Proteins, Proteome, Anticonvulsants, Structure-Activity Relationship, Stereoisomerism, Male, In Vitro Techniques, Lacosamide
Depositing User:	Symplectic Admin
Date Deposited:	18 Jun 2015 16:25
Last Modified:	16 Dec 2022 02:59
DOI:	10.1021/jm9012054
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2014060

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