title: Synthesis and anticonvulsant activity of enaminones. 3. Investigations on 4'-, 3'-, and 2'-substituted and polysubstituted anilino compounds, sodium channel binding studies, and toxicity evaluations.
abstract: In a continuing evaluation of the aniline-substituted enaminones, the synthesis of additional para-substituted analogs has been made in an attempt to further quantify the electronic (sigma) and lipophilic (pi) requirements for anticonvulsant activity in this series. In addition, meta- and ortho-substituted and polysubstituted compounds have been synthesized and evaluated for anticonvulsant activity. In the para-substituted series, 4-cyano analogs (32 and 33) (+ sigma, - pi), which were highly active via intraperitoneal (ip) injection in mice, were inactive on oral (po) administration in rats. The para-substituted trifluoromethoxy (+ sigma, + pi) analog (8) had significant potency by both routes. Meta substitution limited the activity due to steric factors. Bromo and iodo substituents produced active para-substituted analogs (5 and 17) but were inactive when substituted in the meta position (37 and 41, respectively). Ortho substitution provided no clear relationship due to nonparametric deviations. Neither 1, the prototype enaminone, nor 2, the putative metabolite, produced significant nephrotoxicity or hepatotoxicity. Sodium channel binding of 1 and 8 indicated that 8 displayed relatively potent sodium channel binding but 1 showed weaker effects with IC50 values of 489 and 170 microM respectively against [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTX-B).
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy and Pharmaceutical Sciences, Howard University, Washington, D.C. 20059, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Scott
authors.forename: G O
authors.initials: GO
authors.lastname: Rankin
authors.forename: J P
authors.initials: JP
authors.lastname: Stables
authors.forename: M S
authors.initials: MS
authors.lastname: Alexander
authors.forename: I O
authors.initials: IO
authors.lastname: Edafiogho
authors.forename: V A
authors.initials: VA
authors.lastname: Farrar
authors.forename: K R
authors.initials: KR
authors.lastname: Kolen
authors.forename: J A
authors.initials: JA
authors.lastname: Moore
authors.forename: L D
authors.initials: LD
authors.lastname: Sims
authors.forename: A D
authors.initials: AD
authors.lastname: Tonnu
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001496:Batrachotoxins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D001496:Batrachotoxins; D015222:Sodium Channels; C031775:batrachotoxinin A 20-alpha-benzoate