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. Issue 13 (1st July 2015)

• Record Type: Journal Article
• Authors: Torregrosa, Robert; Yang, Xiao-Fang; Dustrude, Erik T.; Cummins, Theodore R.; Khanna, Rajesh; Kohn, Harold
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 13(2015)
• Page Start: 3655
• Page End: 3666
• Publication Date: 2015-07-01
• Subjects: AAA α-aminoamide -- ASD antiseizure drug -- ASP Anticonvulsant Screening Program -- CAD catecholamine A-differentiated -- CNS central nervous system -- ED50 effective dose (50%) -- FAA functionalized amino acid -- IBCF isobutyl chloroformate -- IC50 concentration at which half of the channels have transitioned to a slow-inactivated state -- ip intraperitoneally -- MAC mixed anhydride coupling -- MES maximal electroshock seizure -- NINDS National Institutes of Neurological Disorders and Stroke -- NMM N-methylmorpholine -- NOAEL no observed adverse effect level -- OCF3 trifluoromethoxy -- PI protective index -- po orally -- RMP resting membrane potential -- SAR structure activity relationship -- scMet scMetrazol -- TD50 neurological impairment (toxicity, 50%) -- TEA-Cl tetraethylammonium chloride -- V1/2 voltage of half-maximal (in)activation -- VGSC voltage-gated sodium channel; Chimeric agents -- Functionalized amino acids -- α-Aminoamides -- Antiseizure agents -- Na+ current inhibition; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.04.014
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 hNaV 1.1, rNaV 1.3, hNaV 1.5, or hNaV 1.7 with ( R )-9 recapitulated the high levels of sodium channel slow inactivation.