title: Defining the structural parameters that confer anticonvulsant activity by the site-by-site modification of (R)-N'-benzyl 2-amino-3-methylbutanamide.
abstract: Primary amino acid derivatives (PAADs) (N'-benzyl 2-substituted 2-amino acetamides) are structurally related to functionalized amino acids (FAAs) (N'-benzyl 2-substituted 2-acetamido acetamides) but differ by the absence of the terminal N-acetyl group. Both classes exhibit potent anticonvulsant activities in the maximal electroshock seizure animal model, and the reported structure-activity relationships (SARs) of PAADs and FAAs differ in significant ways. Recently, we documented that PAAD efficacy was associated with a hydrocarbon moiety at the C(2)-carbon, while in the FAAs, a substituted heteroatom one atom removed from the C(2)-center was optimal. Previously in this issue, we showed that PAAD activity was dependent upon the electronic properties of the 4'-N'-benzylamide substituent, while FAA activity was insensitive to electronic changes at this site. In this study, we prepared analogues of (R)-N'-benzyl 2-amino-3-methylbutanamide to identify the structural components for maximal anticonvulsant activity. We demonstrated that the SAR of PAADs and FAAs diverged at the terminal amide site and that PAADs had considerably more structural latitude in the types of units that could be incorporated at this position, suggesting that these compounds function according to different mechanism(s).
authors.affiliation: Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599-7568, United States.
authors.forename: Amber M
authors.initials: AM
authors.lastname: King
authors.forename: Marc
authors.initials: M
authors.lastname: De Ryck
authors.forename: Rafal
authors.initials: R
authors.lastname: Kaminski
authors.forename: Anne
authors.initials: A
authors.lastname: Valade
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000613:Aminobutyrates; D000927:Anticonvulsants