title: Synthesis, neuronal activity and mechanisms of action of halogenated enaminones.
abstract: Due to the excellent anticonvulsant activity of previously synthesized halogenated enaminones, more disubstituted analogs were synthesized and evaluated in vitro. The new enaminones either had no effect, depressed, or enhanced population spike (PS) amplitude in the rat hippocampus in a concentration-dependent manner. Structure-activity relationship (SAR) analysis indicated that compounds 21 and 25 (with dibromo substituents) were equipotent, and more potent than compound 2 (with dichloro substituents), with compound 25 being the most efficacious of all tested compounds. Both diiodo derivatives 30 and 31 tested produced no significant effect on PS. For PS depression, phenyl substitution on the cyclohexenone ring produced the most efficacious compound 25. PS depressing analogues also depressed evoked excitatory postsynaptic current (EPSC) and action potential firing frequency. Removal of phenyl or methyl group from position 6 on the cyclohexenone ring of enaminone esters produced compound 28 which exhibited pro-convulsant effects. There was no direct correlation between C log P values and anticonvulsant activity of the halogenated enaminones. The mechanisms of anticonvulsant activity were the indirect suppression of excitatory synaptic transmission by enhancing extracellular GABA, and the direct suppression of action potential firing of the neurons.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Saint Joseph, Hartford, CT 06103, United States. Electronic address: iedafiogho@usj.edu.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Edafiogho
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait. Electronic address: mqaddoumi@hsc.edu.kw.
authors.forename: Mohamed G
authors.initials: MG
authors.lastname: Qaddoumi
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait. Electronic address: anu@hsc.edu.kw.
authors.forename: Kethireddy V V
authors.initials: KV
authors.lastname: Ananthalakshmi
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait. Electronic address: dphillips@hsc.edu.kw.
authors.forename: Oludotun A
authors.initials: OA
authors.lastname: Phillips
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait. Electronic address: kombian@hsc.edu.kw.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Kombian
mesh_terms: D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006219:Halogens / Q000737:chemistry*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000927:Anticonvulsants; D006219:Halogens
keywords: Dihalogenated enaminones; Neuronal activity; Synthesis