title: Primary amino acid derivatives: compounds with anticonvulsant and neuropathic pain protection activities.
abstract: Pharmacological management remains the primary method to treat epilepsy and neuropathic pain. We have advanced a novel class of anticonvulsants termed functionalized amino acids (FAAs). In this study, we examine FAA derivatives from which the terminal acetyl moiety was removed and termed these compounds primary amino acid derivatives (PAADs). Twenty-seven PAADs were prepared; the central C(2) R-substituent was varied, including C(2) stereochemistry, and the compounds were tested in rodent models of seizures and neuropathic pain. C(2)-Hydrocarbon N-benzylamide PAADs were potent anticonvulsants and excellent anticonvulsant activity (mice, ip; rat, po) was observed for C(2) R-substituted PAADs in which the R group was ethyl, isopropyl, or tert-butyl, and the C(2) stereochemistry conformed to the d-amino acid configuration ((R)-stereoisomer). These values surpassed the activities of several clinical antiepileptic drugs. The C(2) (R)-ethyl and C(2) (R)-isopropyl PAADs also displayed excellent activities in the mouse (ip) formalin neuropathic pain model. Significantly, unlike the FAA structure-activity relationship, PAAD anticonvulsant activity increased upon substitution of a methylene unit for a heteroatom in the R-substituent that was one atom removed from the C(2) site, suggesting that these PAADs function by a different pathway than FAAs.
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: Christophe
authors.initials: C
authors.lastname: Salomé
authors.forename: Jason
authors.initials: J
authors.lastname: Dinsmore
authors.forename: Elise
authors.initials: E
authors.lastname: Salomé-Grosjean
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: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003292:Convulsants; D004597:Electroshock; D005557:Formaldehyde; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy*; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000700:Analgesics; D000927:Anticonvulsants; D003292:Convulsants; D005557:Formaldehyde; D010433:Pentylenetetrazole