Lacosamide isothiocyanate-based agents: novel agents to target and identify lacosamide receptors.
(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.
Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, USA.
Ki Duk
KD
Park
Pierre
P
Morieux
Christophe
C
Salomé
Steven W
SW
Cotten
Onrapak
O
Reamtong
Claire
C
Eyers
Simon J
SJ
Gaskell
James P
JP
Stables
Rihe
R
Liu
Harold
H
Kohn
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D017879:Isothiocyanates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000078334:Lacosamide; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D012640:Seizures / Q000517:prevention & control; D012694:Serine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000081:Acetamides; D000927:Anticonvulsants; D036341:Intercellular Signaling Peptides and Proteins; D017879:Isothiocyanates; C545549:N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy)propionamide; D009419:Nerve Tissue Proteins; D020543:Proteome; C095114:collapsin response mediator protein-2; D012694:Serine; D000078334:Lacosamide