Synthesis, neuronal activity and mechanisms of action of halogenated enaminones

• 2,4-Dichlorophenyl amino and 2,4-dibromophenylamino analogues of enaminones were synthesized.
• 2,4-Dibromophenylamino analogues of the enaminones were most neuroactive.
• Neuronal activity involved synaptic and non-synaptic mechanisms.
• Compounds 21 and 25 were identified as leads for further testing as anticonvulsants.

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.

A series of halogenated enaminones were synthesized and screened for neuronal activity. Some dihalogenated analogues were neuroactive and compounds 21 and 25 were the most potent anticonvulsant enaminones.Figure optionsDownload as PowerPoint slide